3719Primary Care and Global Health CHAPTER 474
epidemic. By the 1990s, primary health care had fallen out of favor
in many global-health policy circles, and low- and middle-income
countries were being encouraged to reduce public sector spending on
health and to focus on cost-effectiveness analysis to provide a package
of health care measures thought to offer the greatest health benefits.
HEALTH CHALLENGES IN LOW- AND
MIDDLE-INCOME COUNTRIES
Low- and middle-income countries, defined by a per capita gross
national income of <$12,535 (U.S.) per person per year, account for
>85% of the world’s population. Average life expectancy in these countries lags far behind that in high-income countries: whereas the average
life expectancy at birth for a girl in high-income countries is 83 years,
it is only 65 years for a girl in low-income countries. This discrepancy
has received growing attention over the past 50 years. Initially, the
situation in poor countries was characterized primarily in terms of
high fertility and high infant, child, and maternal mortality rates, with
most deaths and illnesses attributable to infectious or tropical diseases
among remote, largely rural populations. With growing adult (and
especially elderly) populations and changing lifestyles linked to global
forces of urbanization, a new set of health challenges characterized by
chronic diseases, environmental overcrowding, and road traffic injuries has emerged rapidly (Fig. 474-1). The majority of tobacco-related
deaths globally now occur in low- and middle-income countries, and
the risk of a child’s dying from a road traffic injury in Africa is more
than twice that in Europe. Thus, low- and middle-income countries
in the twenty-first century face a full spectrum of health challenges—
infectious, chronic, and injury-related—at much higher incidences and
prevalences than are documented in high-income countries and with
many fewer resources to address these challenges.
Addressing these challenges, however, does not mean simply waiting for economic growth. Analysis of the association between wealth
and health across countries reveals that, for any given level of wealth,
there is a substantial variation in life expectancy at birth that has persisted despite overall global progress in life expectancy during the past
40 years (Fig. 474-2). Health status in low- and middle-income countries varies enormously. Nations such as Cuba and Costa Rica have life
expectancies and childhood mortality rates similar to or even better
than those in high-income countries; in contrast, countries in subSaharan Africa and the former Soviet bloc have at times experienced significant reverses in these health markers, particularly in the
1990s.
As Angus Deaton stated in the World Institute for Development
Economics Research annual lecture on September 29, 2006, “People in
poor countries are sick not primarily because they are poor but because
of other social organizational failures, including health delivery, which
are not automatically ameliorated by higher income.” This analysis
concurs with classic studies of the array of societal factors explaining
good health in poor settings such as Cuba and Kerala State in India in
the 1980s. Analyses conducted over the past four decades indeed show
that rapid health improvement is possible in very different contexts.
That some countries continue to lag far behind can be understood
through a comparison of regional differences in progress in terms of
life expectancy over this period (Fig. 474-3).
As average levels of health vary across regions and countries, so
too do they vary within countries (Fig. 474-4). Indeed, disparities
within countries are often greater than those between high-income
and low-income countries. For example, if low- and middle-income
countries could reduce their overall childhood mortality rate to that of
the richest one-fifth of their populations, global childhood mortality
could be decreased by 40%. Disparities in health are mostly a result
of social and economic factors such as daily living conditions, access
to resources, and ability to participate in life-affecting decisions. In
most countries, the health care sector actually tends to exacerbate
health inequalities (the “inverse-care law”); because of neglect and
discrimination, poor and marginalized communities are much less
likely to benefit from public health services than those that are better
off. Reforming health systems toward people-centered primary care
provides an opportunity to reverse these negative trends. 1
Institute of Medicine. Primary Care: America’s Health in a New Era (1996).
health systems that is synonymous with the term primary health care.
In 1996, the U.S. Institute of Medicine encompassed many of these
different usages, defining primary care as “the provision of integrated,
accessible health care services by clinicians who are accountable for
addressing a large majority of personal health care needs, developing
a sustained partnership with patients, and practicing in the context
of family and community.”1
We use this definition of primary care in
this chapter. Primary care performs an essential function for health
systems, providing the first point of contact when people seek health
care, dealing with most problems, and referring patients onward to
other services when necessary. As is increasingly evident in countries
of all income levels, without strong primary care, health systems cannot
function properly or address the health challenges of the communities
they serve.
Primary care is only one part of a primary health care approach.
The Declaration of Alma-Ata, drafted in 1978 at the International
Conference on Primary Health Care in Alma-Ata (now Almaty in
Kazakhstan), identified many features of primary care as being essential to achieving the goal of “health for all by the year 2000.” However,
it also identified the need to work across different sectors, address
the social and economic factors that determine health, mobilize the
participation of communities in health systems, and ensure the use
and development of technology that was appropriate in terms of setting and cost. The declaration drew from the experiences of low- and
middle-income countries in trying to improve the health of their
people following independence. Commonly, these countries had built
hospital-based systems similar to those in high-income countries. This
effort had resulted in the development of high-technology services in
urban areas while leaving the bulk of the population without access to
health care unless they traveled great distances to these urban facilities.
Furthermore, much of the population lacked access to basic public
health measures. Primary health care efforts aimed to move care closer
to where people lived, to ensure their involvement in decisions about
their own health care, and to address key aspects of the physical and
social environment essential to health, such as water, sanitation, and
education.
After the Declaration of Alma-Ata, many countries implemented
reforms of their health systems based on primary health care. Most
progress involved strengthening of primary care services; unexpectedly, however, much of this progress was seen in high-income
countries, most of which constructed systems that made primary care
available at low or no cost to their entire populations and that delivered
the bulk of services in primary care settings. This endeavor also saw
the reinforcement of family medicine as a specialty to provide primary
care services. Even in the United States (an obvious exception to this
trend), it became clear that the populations of states with more primary
care physicians and services were healthier than those with fewer such
resources.
Progress was also made in many low- and middle-income countries.
However, the target of “health for all by the year 2000” was missed
by a large margin. The reasons were complex but partly entailed a
general failure to implement all aspects of the primary health care
approach, particularly work across sectors to address social and economic factors that affect health and provision of sufficient human and
other resources in order to make possible the access to primary care
attained in high-income countries. Furthermore, despite the consensus
in Alma-Ata in 1978, the global health community rapidly became
fractured in its commitment to the far-reaching measures called for by
the declaration. Economic recession tempered enthusiasm for primary
health care, and momentum shifted to programs concentrating on a
few priority measures such as immunization, oral rehydration, breastfeeding, and growth monitoring for child survival. Success with these
initiatives supported the continued movement of health development
efforts away from the comprehensive approach of primary health care
and toward programs that targeted specific public health priorities.
This approach was reinforced by the need to address the HIV/AIDS
3720 PART 17 Global Medicine
Health services have failed to make their contribution to reducing
these pervasive social inequalities by ensuring universal access to existing,
scientifically validated, low-cost interventions such as insecticide-treated
bed nets for malaria, taxes on cigarettes, short-course chemotherapy
for tuberculosis, antibiotic treatment for pneumonia, dietary modification and secondary prevention measures for high blood pressure
and high cholesterol levels, and water treatment and oral rehydration
therapy for diarrhea. Despite decades of “essential packages” and
“basic” health campaigns, the effective implementation of what is
already known to work with requisite scale and quality appears (deceptively) to be difficult.
Recent analyses have begun to focus on “the how” (as opposed
to “the what”) of health care delivery, exploring why health progress is slow and sluggish despite the abundant availability of proven
35
30
25
20
15
10
5
0
Deaths (millions)
2004 2015 2030 2004 2015 2030 2004 2015 2030
Intentional injuries
Other unintentional injuries
Road traffic accidents
Other noncommunicable
diseases
Cancers
Cardiovascular disease
Maternal, perinatal, and
nutritional conditions
Other infectious diseases
HIV/AIDS, TB, and malaria
Year/countries grouped by income per capita
FIGURE 474-1 Projections of disease burden to 2030 for high-, middle-, and low-income countries (left, center, and right, respectively). TB, tuberculosis. (Reproduced with
permission from World Health Organization: The Global Burden of Disease 2004 Update, 2008.)
2005
1975
Life expectancy at birth (years)
85
75
65
55
45
35
Namibia
South Africa
Botswana
Swaziland
0 5000 10,000 15,000 20,000 25,000 30,000 35,000 40,000
GDP per capita, constant 2000 international $
FIGURE 474-2 Gross domestic product (GDP) per capita and life expectancy at birth in 169 countries, 1975 and 2005. Only outlying countries are named. (Reproduced with
permission from World Health Organization: Primary Health Care: Now More Than Ever. World Health Report 2008.)
3721Primary Care and Global Health CHAPTER 474
Arab states
East Asia and Pacific
Latin America and
Caribbean
South Asia
Sub-Saharan Africa
CEE and CIS
High-income OECD
1970–1975 2000–2005
52.1
66.9
60.5
70.4
61.1
71.7
50.1
63.2
45.8
46.1
69
68.1
71.6
78.8
40 50 60 70 80 90
Life expectancy (years)
FIGURE 474-3 Regional trends in life expectancy. CEE, Central and Eastern Europe;
CIS, the Commonwealth of Independent States; OECD, Organization for Economic
Cooperation and Development. (Reproduced with permission from World Health
Organization: Closing the Gap in a Generation: Health Equity Through Action on the
Social Determinants of Health. Commission on Social Determinants of Health Final
Report, 2008.)
FIGURE 474-4 A. Mortality of children under 5 years old, by place of residence, in
five countries. (Reproduced with permission from World Health Organization: Data
from the world health organization.) B. Full basic immunization coverage (%), by
income group. (Reproduced with permission from World Health Organization:
Primary Health Care: Now More Than Ever. World Health Report 2008.)
300
250
200
150
100
50
0
Under 5 mortality rate per 1000
Haiti Nigeria Pakistan Philippines Rwanda
Rural Urban
A
100
80
60
40
20
0
Bangladesh
2004
Colombia
2005
Indonesia
2002–2003
Mozambique
2003
Lowest quintile Quintile 2 Quintile 3
Quintile 4 Highest quintile
B
interventions for health conditions in low- and middle-income countries. Three general categories of reasons are being identified: (1) shortfalls in performance of health systems; (2) stratifying social conditions;
and (3) skews in science.
■ SHORTFALLS IN PERFORMANCE OF HEALTH
SYSTEMS
Specific health problems often require the development of specific
health interventions (e.g., tuberculosis requires short-course chemotherapy). However, the delivery of different interventions is often
facilitated by a common set of resources or functions: money or financing, trained health workers, and facilities with reliable supplies fit for
multiple purposes. Unfortunately, health systems in most low- and
middle-income countries are largely dysfunctional across these core
functions.
In the large majority of low- and middle-income countries, the level
of public financing for health is woefully insufficient: whereas highincome countries spend, on average, >7% of the gross domestic product on health, middle-income countries spend <3%, and low-income
countries <2%. External financing for health through various donor
channels grew rapidly in the first decade of the twenty-first century but
has grown more slowly in the second decade to its current level of $37
billion. While these funds for health are significant, they represent <2%
of total health expenditures in low- and middle-income countries and
therefore are neither a sufficient nor a long-term solution to chronic
underfinancing. In Africa, 70% of health expenditures come from
domestic sources. The predominant form of health care financing—
charging patients at the point of service—is the least efficient and the
most inequitable, tipping millions of households into poverty annually.
Health workers, who represent another critical resource, are often
inadequately trained and supported in their work especially in locations with the greatest needs. Recent estimates indicate a shortage of
>18 million health workers, constituting a crisis that is greatly exacerbated by the migration of health workers from low- and middle-income
countries to high-income countries. Sub-Saharan Africa carries 24% of
the global disease burden but has only 3% of the health workforce
(Fig. 474-5).
Critical diagnostics and drugs often do not reach patients in need
because of supply-chain failures. Moreover, facilities fail to provide
good-quality and safe care: new evidence suggests much higher rates of
adverse events among hospitalized patients in low- and middle-income
countries than in high-income countries. Weak government planning,
regulatory, monitoring, and evaluation capacities are associated with
rampant, unregulated commercialization of health services and chaotic fragmentation of these services as donors “push” their respective
priority programs. With such fragile foundations, it is not surprising
that low-cost, affordable, validated interventions are not reaching those
who need them.
35
30
25
20
15
10
5
0
% of global burden of disease
0 5 10 15 20 25 30 35 40 45
South-East Asia
Africa
Western Pacific
Eastern Mediterranean
Europe Americas
% of global workforce
FIGURE 474-5 Global burden of disease and health workforce. (Reproduced with
permission from World Health Organization: Working together for health, 2006.)
3722 PART 17 Global Medicine
■ STRATIFYING SOCIAL CONDITIONS
Health care delivery systems do not exist in a vacuum but rather are
embedded in a complex of social and economic forces that often stratify opportunities for health unfairly. Most worrisome are the pervasive
forces of social inequality that serve to marginalize populations with
disproportionately large health needs (e.g., the urban poor; illiterate mothers). Why should a poor slum dweller with no income be
expected to come up with the money for a bus fare needed to travel
to a clinic to learn the results of a sputum test for tuberculosis? How
can a mother living in a remote rural village and caring for an infant
with febrile convulsions find the means to get her child to appropriate
care? Shaky or nonexistent social security systems, dangerous work
environments, isolated communities with little or no infrastructure,
and systematic discrimination against racialized minorities are among
the myriad forces with which efforts for more equitable health care
delivery must contend.
■ SKEWS IN SCIENCE
While science has yielded enormous breakthroughs in health in
high-income countries, with some spillover to low- and middle-income
countries, many important health problems continue to affect primarily low- and middle-income countries whose research and development investments are deplorably inadequate. The past two decades
have seen growing efforts to right this imbalance with research and
development investment for new drugs, vaccines, and diagnostics that
effectively cater to the specific health needs of populations in low- and
middle-income countries. For example, the TB Alliance has revitalized
a previously “dry” pipeline for new tuberculosis drugs. In 2019, their
new drug (pretomanid) received U.S. Food and Drug Administration
approval as part of a triple oral regimen (bedaquiline, pretomanid, and
linezolid) [BPaL]) that treats extensively drug-resistant tuberculosis
faster, better, and cheaper.
As discussed above, the primary constraint on better health in
low- and middle-income countries is related less to the availability of
health technologies and more to their effective delivery. Underlying
these health delivery challenges is a major bias regarding what constitutes legitimate “science” to improve health equity. The lion’s share of
health research financing is channeled toward the development of new
technologies—drugs, vaccines, and diagnostics; in contrast, virtually
no resources are directed toward research on how health care delivery systems can become more reliable and overcome adverse social
conditions. The complexity of systems and social context is such that
this issue of delivery requires an enormous investment in terms not
only of money but also of scientific rigor, with the development of new
research methods and measures and the attainment of greater legitimacy in the mainstream scientific establishment.
These common challenges to low- and middle-income countries
partly explain the resurgence of interest in the primary health care
approach and the emergence of a global movement toward universal
health coverage, now enshrined as one of the Sustainable Development Goal targets adopted in Agenda 2030 by all countries at the
United Nations in September 2015. In some countries (mostly middleincome), significant progress has been made in expanding coverage by
health systems based on primary care and even in improving indicators
of population health. More countries are embarking on the creation of
primary care services despite the challenges that exist, particularly in
low-income countries. Even when these challenges are acknowledged,
there are many reasons for optimism that low- and middle-income
countries can accelerate progress in building primary care as a key
vehicle toward achieving universal health coverage.
PRIMARY HEALTH CARE IN THE TWENTYFIRST CENTURY
The new millennium has seen a resurgence of interest in primary
health care as a means of addressing global health challenges but
also of familiar obstacles to its implementation. This interest has
been driven by many of the same issues that led to the Declaration of
Alma-Ata: rapidly increasing disparities in health between and within
countries, spiraling costs of health care at a time when many people
lack quality care, dissatisfaction of communities with the care they are
able to access, failure to address changes in health threats, especially
noncommunicable disease epidemics, and most recently, global failures
in preparing for and responding to the COVID-19 pandemic. These
challenges require a comprehensive approach and strong health systems with effective primary care. Global health development agencies
have partially recognized that sustaining gains in public health priorities such as HIV/AIDS and pandemic preparedness requires not only
robust health systems but also the tackling of social and economic factors related to disease incidence and progression. Weak health systems
have proved a major obstacle to delivering new technologies, such as
COVID-19 vaccines and antiretroviral therapy, to all who need them.
We discuss experiences in low- and middle-income countries in relation to primary care in greater detail below. First, we consider the features of primary health care and primary care as currently understood.
■ REVITALIZATION OF PRIMARY HEALTH CARE
At the 2019 World Health Assembly (an annual meeting of all countries to discuss the work of the World Health Organization [WHO]), a
resolution was passed reaffirming the principles of the Declaration of
Alma-Ata and the need for national health systems to be based on primary health care. This resolution reframed primary health care as three
components: (1) primary care and essential public health functions as
the core of integrated health services; (2) empowered people and communities; and (3) multisectoral policy and action. This reframing itself
drew on the 2008 WHO World Health Report, which asserted that a
primary health care approach was necessary “now more than ever” to
address global health priorities, especially in terms of disparities and
new health challenges.
The 2008 World Health Report highlighted four broad areas for
reform (Fig. 474-6). One of these areas—the need to organize health
care so that it places the needs of people first—relates to the necessity
for strong primary care in health systems and what this requirement
entails. The other three areas also relate to primary care. All four areas
require action to move health systems in a direction that will reduce
disparities and increase the satisfaction of those they serve.
Universal Coverage Reforms to Improve Health Equity
Despite progress in many countries, most people in the world can
receive health care services only if they can pay at the point of service.
Disparities in health are caused not only by a lack of access to necessary
UNIVERSAL
COVERAGE
REFORMS
to improve
health equity
SERVICE
DELIVERY
REFORMS
to make health systems
people-centered
LEADERSHIP
REFORMS
to make health
authorities more
reliable
PUBLIC POLICY
REFORMS
to promote and
protect the health of
communities
FIGURE 474-6 The four reforms of primary health care renewal. (Reproduced with
permission from World Health Organization: Primary Health Care: Now More Than
Ever. World Health Report 2008.)
3723Primary Care and Global Health CHAPTER 474
health services but also by the impact of expenditure on health. More
than 100 million people are still being driven into extreme poverty each
year by health care costs, with countless others deterred from accessing services at all. Moving toward prepayment financing systems for
universal coverage, which ensure access to a comprehensive package
of services according to need without precipitating economic ruin,
has therefore emerged as a major priority in low- and middle-income
countries. Increasing coverage of health services can be considered in
terms of three axes: the proportion of the population covered, the range
of services underwritten, and the percentage of costs paid (Fig. 474-7).
Moving toward universal health coverage requires ensuring the availability of health care services to all, eliminating barriers to access,
and organizing pooled financing mechanisms, such as taxation or
insurance, to remove user fees at the point of service. It also requires
measures beyond financing, including expansion of health services in
poorly served areas, improvement in the quality of services provided
to marginalized communities, and increased coverage of other social
services that significantly affect health (e.g., education).
Service Delivery Reforms to Make Health Systems PeopleCentered Health systems have often been organized around the
needs of those who provide health care services, such as clinicians and
policymakers. The result is a centralization of services or the provision
of vertical programs that target single diseases. The principles of primary health care, including the development of primary care, reorient
care around the needs of the people to whom services cater. This
“people-centered” approach aims to provide health care that is both
more effective and appropriate.
The increase in noncommunicable diseases in low- and middleincome countries offers a further stimulus for urgent reform of service
delivery to improve chronic disease care. As discussed above, large
numbers of people currently fail to receive relatively low-cost interventions that have reduced the incidence of these diseases in high-income
countries. Delivery of these interventions requires health systems that
can address multiple problems and manage people over a long period
within their own communities, yet many low- and middle-income
countries are only now starting to adapt and build primary care services that can address noncommunicable diseases and communicable
diseases requiring chronic care. Even some countries (e.g., Iran) that
have had significant success in reducing communicable diseases and
improving child survival have been slow to adapt their health systems
to rapidly accelerating noncommunicable disease epidemics.
People-centered care requires a safe, comprehensive, and integrated response to the needs of those presenting to health systems,
with treatment at the first point of contact or referral to appropriate
services. Because no discrete boundary separates people’s needs for
health promotion, curative interventions, and rehabilitation services
across different diseases, primary care services must address all presenting problems in a unified way. Meeting people’s needs also involves
improved communication between patients and their clinicians, who
must take the time to understand the impact of the patients’ social
context on the problems they present with. This enhanced understanding is made possible by improvements in the continuity of care so that
responsibility transcends the limited time people spend in health care
facilities. Primary care plays a vital role in navigating people through
the health system; when people are referred elsewhere for services,
primary care providers must monitor the resulting consultations and
perform follow-up. All too often, people do not receive the benefit of
complex interventions undertaken in hospitals because they lose contact with the health care system once discharged. Comprehensiveness
and continuity of care are best achieved by ensuring that people have
an ongoing personal relationship with a care team.
Public Policy Reforms to Promote and Protect the Health
of Communities Public policies in sectors other than health care
are essential to reduce disparities in health and to make progress
toward global public health targets. The 2008 final report of the WHO
Commission on Social Determinants of Health provided an exhaustive
review of the multisectoral policies required to address health inequities at the local, national, and global levels. Advances against major
challenges such as HIV/AIDS, tuberculosis, emerging infections, cardiovascular disease, cancers, and injuries require effective collaboration
with sectors such as transport, housing, labor, agriculture, urban planning, trade, and energy. The COVID-19 pandemic has underscored the
importance of multisectoral action to protect health; countries that have
been most successful in managing the pandemic have been those best
able to coordinate across their societies to implement nonpharmaceutical health measures and build social solidarity. Similarly, while tobacco
control provides a striking example of what is possible if different sectors work together toward health goals, the lack of implementation of
many evidence-based tobacco control measures in most countries just
as clearly illustrates the difficulties encountered in such multisectoral
work and the unrealized potential of public policies to improve health.
Leadership Reforms to Make Health Authorities More
Reliable The Declaration of Alma-Ata emphasized the importance
of participation by people in their own health care. In fact, participation is important at all levels of decision-making. Contemporary
health challenges require new models of leadership that acknowledge
the role of government in reducing disparities in health but that also
recognize the many types of organizations that provide health care
services. Governments need to guide and negotiate among these different groups, including nongovernmental organizations (NGOs) and
the private sector, and to provide strong regulation where necessary.
This difficult task requires a massive reinvestment in leadership and
governance capacity, especially if action by different sectors is to be
effectively implemented. Moreover, disadvantaged groups and other
actors are increasingly expecting that their voices and health needs will
be included in the decision-making process. The complex landscape
for leadership at the national level is mirrored in many ways at the
international or global level. The transnational character of health and
the increasing interdependence of countries with respect to outbreak
diseases, climate change, security, migration, and agriculture place a
premium on more effective global health governance.
EXPERIENCES WITH PRIMARY CARE IN
LOW- AND MIDDLE-INCOME COUNTRIES
Aspects of the primary health care approach described above, with an
emphasis on primary care services, have been implemented to varying
degrees in many low- and middle-income countries over the past halfcentury. As discussed above, some of these experiences inspired and
informed the Declaration of Alma-Ata, which itself led many more
countries to attempt to implement primary health care. This section
describes the experiences of a selection of low- and middle-income
countries in improving primary care services that have enhanced the
health of their populations.
Before Alma-Ata, few countries had attempted to develop primary
care on a national level. Rather, most focused on expanding primary
care services to specific communities (often rural villages), making use
of community volunteers to compensate for the absence of facility-based
Breadth: who is insured?
Total health expenditure
Reduce
cost
sharing
Extend to
uninsured
Depth:
which benefits
are covered?
Height:
what
proportion
of the costs
is covered?
Include
other
services
Public expenditure
on health
FIGURE 474-7 Three ways of moving toward universal coverage.
3724 PART 17 Global Medicine
care. In contrast, in the post–World War II period, China invested in
primary care on a national scale, and life expectancy doubled within
roughly 20 years. The Chinese expansion of primary care services
included a massive investment in infrastructure for public health (e.g.,
water and sanitation systems) linked to innovative use of community
health workers. These “barefoot doctors” lived in and expanded care to
rural villages. They received a basic level of training that enabled them
to provide immunizations, maternal care, and basic medical interventions, including the use of antibiotics. Through the work of the barefoot
doctors, China brought low-cost universal basic health care coverage
to its entire population, most of which had previously had no access
to these services.
In 1982, the Rockefeller Foundation convened a conference to
review the experiences of China along with those of Costa Rica,
Sri Lanka, and the state of Kerala in India. In all of these locations,
good health care at low cost appeared to have been achieved. Despite
lower levels of economic development and health spending, all of these
jurisdictions, along with Cuba, had health indicators approaching—or
in some cases exceeding—those of developed countries. Analysis of
these experiences revealed a common emphasis on primary care services, with expansion of care to the entire population free of charge
or at low cost, combined with community participation in decisionmaking about health services and coordinated work in different sectors
(especially education) toward health goals. During the more than three
decades since the Rockefeller meeting, some of these countries have
built on this progress, while others have experienced setbacks. Recent
experiences in developing primary care services show that the same
combination of features is necessary for success. For example, Brazil—a
large country with a dispersed population—made major strides in
increasing the availability of health care from 1980 to 2010. The Brazilian
Family Health Program expanded progressively across the country to
reach universal coverage. This program provided communities with
free access to primary care teams made up of primary care physicians,
community health workers, nurses, dentists, obstetricians, and pediatricians. These teams were responsible for the provision of primary
care to all people in a specified geographic area—not only those who
access health clinics. Moreover, individual community health workers
were responsible for a named list of people within the area covered by
the primary care team. Solid evidence indicated that the Family Health
Program has contributed to impressive gains in population health,
particularly in terms of childhood mortality and health inequities
(Fig. 474-8). Nevertheless, systemic inequalities, magnified during the
COVID-19 crisis, highlight how continued progress is not guaranteed,
and efforts to implement and expand a primary health care approach
need to adapt to new health and political challenges.
Chile has also built on its existing primary care services in the past
two decades, aiming to improve the quality of care and the extent of
coverage in remote areas, above all for disadvantaged populations.
This effort has been made in concert with measures aimed at reducing social inequalities and fostering development,
including social welfare benefits for families and
disadvantaged groups and increased access to earlychildhood educational facilities. As in Brazil, these
steps have improved maternal and child health
and have reduced health inequities. In addition to
directly enhancing primary care services, Brazil and
Chile have instituted measures to increase both the
accountability of health providers and the participation of communities in decision-making. In Brazil,
national and regional health assemblies with high
levels of public participation are integral parts of the
health policy-making process. Chile has instituted a
patient’s charter that explicitly specifies the rights of
patients in terms of the range of services to which
they are entitled.
Other countries that have made recent progress
with primary health care include Bangladesh, once
one of the poorest countries in the world and still
relatively poor. Since achieving its independence
from Pakistan in 1971, Bangladesh has seen a dramatic increase in life
expectancy, and childhood mortality rates are now lower than those
in neighboring nations such as India and Pakistan. The expansion
of access to primary care services has played a major role in these
achievements. This progress has been spearheaded by a vibrant NGO
community that has focused its attention on improving the lives and
livelihoods of poor women and their families through innovative and
integrated microcredit, education, and primary care programs. The
above examples, along with others from the past 40 years in countries
such as Thailand, Rwanda, Ethiopia, Turkey, Viet Nam, and Oman,
illustrate how the implementation of a primary health care approach,
with a greater emphasis on primary care, has led to better access to
health care services—a trend that has not been seen in many other
low- and middle-income countries. This trend, in turn, has contributed to improvements in population health and reductions in health
inequities. However, as these nations have progressed, other countries
have shown how previous gains in primary care can easily be eroded. In
sub-Saharan Africa, undermining of primary care services contributed
to catastrophic reversals in health outcomes catalyzed by the HIV/
AIDS epidemic. Countries such as Botswana and Zimbabwe implemented primary health care strategies in the 1980s, increasing access
to care and making impressive gains in child health. Both countries
were severely affected by HIV/AIDS, with pronounced decreases in
life expectancy. However, Zimbabwe has also seen political turmoil,
a decline of health and other social services, and the flight of health
personnel, whereas Botswana has maintained primary care services
to a greater extent and has managed to organize widespread access to
antiretroviral therapy for people living with HIV/AIDS. China provides a particularly striking example of how changes in health policy
relevant to the organization of health systems (Fig. 474-9) can have
rapid, far-reaching consequences for population health. Even as the
1982 Rockefeller conference was celebrating China’s achievements in
primary care, its health system was unraveling. The decision to open up
the economy in the early 1980s led to rapid privatization of the health
sector and the breakdown of universal health coverage. As a result, by
the end of the 1980s, most people, especially the poorer segments of
the population, were paying directly out of pocket for health care, and
almost no Chinese had insurance—a dramatic transformation. The
“barefoot doctor” schemes collapsed, and the population either turned
to care paid for at hospitals or simply became unable to access care.
This undermining of access to primary care services in the Chinese
system and the resulting increase in impoverishment due to illness
contributed to the stagnation of progress in health in China at the same
time that incomes in that country increased at an unprecedented rate.
Reversals in primary care have meant that China now increasingly faces
health care issues similar to those faced by India, although the country
has more recently implemented measures to restore universal health
coverage, with significant success. In both countries, rapid economic
growth has been linked to lifestyle changes and noncommunicable
6
4
2
0
–2
–4
–6
–8
–10
Mean annual change (since 1998)
3.96
–2.08
–4.24
–6.82 –6.97 –6.77
–8.38
–5.64
High HDI Low HDI
0–20 21–50 51–70 71+
PSF coverage (% population covered)
FIGURE 474-8 Improvements in childhood mortality following the Family Health Program in Brazil. HDI,
Human Development Index; PSF, Program Saúde da Família (Family Health Program). (Source: Ministry of
Health, Brazil.)
3725Primary Care and Global Health CHAPTER 474
disease epidemics. The health care systems of the two nations share
two negative features that are common when primary care is weak: a
disproportionate focus on specialty services provided in hospitals and
unregulated commercialization of health services. China and India
both saw expansion of private hospital services that cater to middleclass and urban populations who can afford care; at the same time,
hundreds of millions of people in rural areas struggled to access basic
services. Even in the former groups, a lack of primary care services has
been associated with late presentation with illness and with insufficient
investment in primary prevention approaches. This neglect of prevention poses a risk of large-scale epidemics of cardiovascular disease,
which could endanger continued economic growth. In addition, the
health systems of both countries now depend for the majority of their
funding on out-of-pocket payments by people when they use services.
Thus, substantial proportions of the population must sacrifice other
essential goods as a result of health expenditure and may even be
driven into poverty by this cost. The commercial nature of health services with inadequate or no regulation has also led to the proliferation
of charlatan providers, inappropriate care, and pressure for people to
pay for expensive and sometimes unnecessary care. Commercial providers have limited incentives to use interventions (including public
health measures) that cannot be charged for or that are what the person
who is paying can afford.
Faced with these problems, China and India have implemented
measures to strengthen primary health care. China has increased government funding of health care, has taken steps toward restoring health
insurance, and has enacted a target of universal access to primary care
services. India has similarly mobilized funding to greatly expand primary care services in rural areas and duplicated this process in urban
settings. Both countries are increasingly using public resources from
their growing economies to fund primary care services.
These encouraging trends are illustrative of new opportunities to
implement a primary health care approach and strengthen primary
care services in low- and middle-income countries. Over the past
decade, all countries have adopted universal health coverage—the
provision of quality health services in a timely manner at affordable
cost—and the primary health care approach remains key to achieving
this.
■ OPPORTUNITIES TO BUILD PRIMARY CARE IN
LOW- AND MIDDLE-INCOME COUNTRIES
Global public health targets will not be met unless health systems are significantly strengthened. More money is currently being spent on health
than ever before. In 2017, global health spending totaled $7.8 trillion
(U.S.)—more than double the amount spent a decade earlier. Although
most expenditure occurs in high-income countries, spending in many
emerging middle-income countries has rapidly accelerated, as has the
allocation of monies for this purpose by both governments in and donors
to low-income countries. These twin trends—greater emphasis on building health systems based on primary care and allotment of more money
for health care—provide opportunities to address many of the challenges
discussed above in low- and middle-income countries.
Accelerating progress requires a better understanding of how global
health initiatives can more effectively facilitate the development of primary care in low-income countries. A review by the WHO Maximizing
Positive Synergies Collaborative Group looked at programs funded by
the Global Fund to Fight AIDS, Tuberculosis and Malaria; the Global
Alliance for Vaccines and Immunization (GAVI); the U.S. President’s
Emergency Plan for AIDS Relief (PEPFAR); and the World Bank (HIV/
AIDS). This group found that global health initiatives had improved
access to and quality of the targeted health services and had led to better information systems and more adequate financing. The review also
identified the need for better alignment of global health initiatives with
other national health priorities and systematic exploitation of potential
synergies. If global health initiatives implement programs that work
in tandem with other components of national health systems without
undermining staffing and procurement of supplies, they have the
potential to contribute substantially to the capacity of health systems
to provide comprehensive primary care services.
In the context of the current pandemic, global health initiatives
appear even more important. The imperative of vaccinating the world’s
population against SARS-CoV-2 has led to the creation of the multibillion-dollar COVAX facility to ensure equitable access to COVID-19
vaccines. The pandemic has also limited access to essential health
services, particularly for mothers and children. As such, efforts like the
Global Financing Facility for every mother and child remain important catalysts for universal access to life-saving services. The general
trend is to coordinate this funding in order to reduce fragmentation
of national health systems and to concentrate more on strengthening
these systems. Comprehensive primary care in low-income countries
must inevitably deal with the rapid emergence of chronic diseases and
the growing prominence of injury-related health problems; thus, international health development assistance must become more responsive
to these needs.
Beyond funding for health services, other opportunities exist.
Increased social participation in health systems can help build primary
care services. In many countries, political pressure from community
advocates for more holistic and accountable care as well as entrepreneurial initiatives to scale up community-based services through
NGOs have accelerated progress in primary care without major
increases in funding. Participation of the population in the provision
of health care services and in relevant decision-making often drives
services to cater to people’s needs as a whole rather than to narrow
public health priorities.
100
80
60
40
20
0
Percentage of total health expenditure
1965
1970
1975
1978
1979
1980
19811982
1983
1984
1985
1986
1987 1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
Out-of-pocket
expenditure
Prepaid private
expenditure
Social security
expenditure
Other general
government
expenditure
FIGURE 474-9 Changes in source of health expenditure in China over the past 40 years. (Reproduced with permission from World Health Organization: Primary Health Care:
Now More Than Ever. World Health Report 2008.)
3726 PART 17 Global Medicine
Participation and innovation can help address critical issues related
to the health workforce in low- and middle-income countries by establishing effective people-centered primary care services. Many primary
care services do not need to be delivered by a physician or a nurse.
Multidisciplinary teams can include paid community workers who
have access to a physician if necessary but who can provide a range of
health services on their own. In Ethiopia, >38,000 community health
workers have been trained and deployed to improve access to primary
care services, and there is increasing evidence that this measure is
contributing to better health outcomes. In India, >600,000 community health advocates have been recruited as part of expanded rural
primary care services. In Niger, the deployment of community health
workers to deliver essential child health interventions (as a component
of integrated community case management) has had impressive results
in reducing childhood mortality and decreasing disparities. After the
Declaration of Alma-Ata, experiences with community health workers
were mixed, with particular problems regarding levels of training and
lack of payment. Current endeavors are not immune from these concerns. However, with access to physician support and the deployment
of teams, some of these concerns may be addressed. Growing evidence
from many countries indicates that shifting appropriate tasks to primary care workers who have had shorter, less expensive training than
physicians will be essential to address the human resources crisis.
Finally, recent improvements in information and communication
technologies, particularly mobile phone and Internet systems, have created the potential for systematic implementation of e-health, telemedicine, and improved health data initiatives in low- and middle-income
countries. These developments raise the tantalizing possibility that
health systems in these countries, which have long lagged behind those
in high-income countries but are less encumbered by legacy systems
that have proved hard to modernize in many settings, could leapfrog
their wealthier counterparts in exploiting these technologies. Although
the challenges posed by poor or absent infrastructure and investment
in many low- and middle-income countries cannot be underestimated
and will need to be addressed to make this possibility a reality, the rapid
rollout of mobile networks and their use for health and other social
services in many low-income countries where access to fixed telephone
lines was previously very limited offer great promise in building primary care services in low- and middle-income countries. To a partial
extent, this potential has been demonstrated and even realized in many
countries during the COVID-19 pandemic, with greatly increased
uptake of the use of telemedicine and clinical support via digital means.
CONCLUSION
As concern continues to mount about glaring inequities in global
health, there is a growing commitment to redress these egregious
shortfalls, as exemplified by the central place of equity in the United
Nations’ Sustainable Development Goals adopted in 2015, including
a specific target on the achievement of universal health coverage in all
countries by 2030. This commitment begins first and foremost with a
clear vision of the fundamental importance of health in all countries,
regardless of income. The values of health and health equity are shared
across all borders, and primary health care provides a framework for
their effective translation across all contexts.
The translation of these fundamental values has its roots in four
types of reform that reflect the distinct but interlinked challenges of
(re)orienting a society’s resources on the basis of its citizens’ health
needs: (1) organizing health care services around the needs of people
and communities; (2) harnessing services and sectors beyond health
care to promote and protect health more effectively; (3) establishing
sustainable and equitable financing mechanisms for universal health
coverage; and (4) investing in effective leadership of the whole of society. This common primary health care agenda highlights the striking
similarity, despite enormous differences in context, in the nature and
direction of the reforms that national health systems must undertake
to promote greater equity in health. This shared agenda is complemented by the growing reality of global health interconnectedness
due, for example, to shared microbial threats, bridging of ethnolinguistic diversity, flows in migrant health workers, and mobilization
of global funds to support the neediest populations. Embracing solidarity in global health while strengthening health systems through a
primary health care approach is fundamental to sustained progress in
global health.
The shortfalls in health system performance, stratification of social
conditions leading to unfair differences in health, and skews in science
that undermine the realization of “Health for All” have never been
more glaringly visible than during the COVID-19 pandemic. But they
also have never commanded such global political attention at the highest level. Out of this crisis, then, is a once-in-a-lifetime opportunity to
recast global and national systems to enable the genuine implementation of the primary health care approach in all countries.
■ FURTHER READING
Aquino R et al: Impact of the family health program on infant mortality in Brazilian municipalities. Am J Public Health 99:87, 2009.
Commission on Social Determinants of Health: Closing the Gap
in a Generation: Health Equity through Action on the Social Determinants of Health: Commission on Social Determinants of Health Final
Report. Geneva, World Health Organization, 2008.
Kruk ME et al: The contribution of primary care to health and health
systems in low- and middle-income countries: A critical review of
major primary care initiatives. Soc Sci Med 70:904, 2010.
Li X et al: The primary health-care system in China. Lancet 390:2584,
2017.
Macinko J et al: The impact of primary healthcare on population
health in low- and middle-income countries. J Ambul Care Manage
32:150, 2009.
Patel V et al: Assuring health coverage for all in India. Lancet
386:2422, 2015.
Rasanathan K et al: Primary health care and the social determinants
of health: Essential and complementary approaches for reducing
inequities in health. J Epidemiol Community Health 65:656, 2011.
Starfield B et al: Contribution of primary care to health systems and
health. Milbank Q 83:457, 2005.
Tangcharoensathien V et al: Primary Health Care: Now More Than
Ever. World Health Report 2008. Geneva, World Health Organization,
2008.
Tangcharoensathien V et al: Health systems development in
Thailand: A solid platform for successful implementation of universal
health coverage. Lancet 391:1205, 2018.
Climate change refers to the effects of accumulated greenhouse gases
(GHGs) in the atmosphere on long-term weather patterns. Anthropogenic emissions—in particular from the burning of fossil fuels and
land conversion—have increased mean global temperatures by approximately 1° Celsius above preindustrial levels. Extreme weather events,
including heatwaves and natural disasters (e.g., wildfires, droughts,
and floods), are becoming more frequent and lead to resource scarcity
(including access to safe drinking water and food), increased environmental pollution and degradation, violent conflict, and precarious
migration. The climate crisis thus has direct consequences for human
health, the practice of medicine, and the stability of health care systems
and as such represents a health emergency. See Chap. 125 for an overview of climate science.
475 Health Effects of
Climate Change
Eugene T. Richardson,
Maxine A. Burkett, Paul E. Farmer
3727Health Effects of Climate Change CHAPTER 475
respiratory disease. Concentrations of PM2.5 are the most important
environmental risk factor for myocardial infarction, cerebrovascular
disease, heart failure, hypertension, diabetes mellitus, arrhythmias, and
venous thromboembolism.
Studies have shown that the relative risk of acute CV events is
increased 1–3% in the setting of short-term elevations of PM2.5.
Longer-term exposures convey an amplified risk (~10%), which is
partially attributable to the exacerbation of chronic conditions (e.g.,
hypertension and diabetes). This holds true for areas with low mean
concentrations of PM2.5 (i.e., where risk is determined by recurring
short-term elevations). The biologic pathways whereby PM2.5 promotes
these complications are complex and multifactorial (Fig. 475-3).
Environmental
Forced migration, Degradation
civil conflict,
mental health impacts
Heat-related illness
and death,
cardiovascular failure
Injuries, fatalities,
mental health impacts
Asthma,
cardiovascular disease
Impact of Climate Change on Human Health
Malnutrition,
diarrheal disease
Respiratory
allergies, asthma
Malaria, dengue,
encephalitis, hantavirus,
Rift Valley fever,
Lyme disease,
chikungunya,
West Nile virus
Cholera,
cryptosporidiosis,
campylobacter, leptospirosis,
harmful algal blooms
Extreme
Heat
Severe
Weather Air
Pollution
Changes
in Vector
Ecology
Increasing
Allergens
Water
Quality Impacts Water and Food
Supply Impacts
Rising
Temperatures
R si ni g
Sea Le ev sl
More Extreme
Weather
nI c er as ni g
CO
L2 eve sl
FIGURE 475-1 Climate change impacts a wide range of health outcomes. This slide illustrates the most significant climate change impacts (rising temperatures, more
extreme weather, rising sea levels, and increasing carbon dioxide levels), their effect on exposures, and the subsequent health outcomes that can result from these changes
in exposures. (Source: https://www.cdc.gov/climateandhealth/effects/default.htm.)
EFFECTS OF CLIMATE CHANGE ON
HEALTH
The World Health Organization predicts that between 2030 and
2050, there will be an additional 250,000 deaths per year globally
from climate-sensitive diseases. These include deaths from infectious
diseases (Chap. 125); respiratory, cardiovascular, and renal disease;
heat-related illness, injury, and trauma; mental illness; and malnutrition (Fig. 475-1). As with much of the global burden of disease, this
increase in mortality will be disproportionately borne by low- and
middle-income countries (LMICs) whose health infrastructures have
been weakened by neocolonialism and structural adjustment. Within
wealthier countries such as the United States, climate change will
amplify existing health disparities between white people and black,
indigenous, and Latinx populations.
■ AIR POLLUTION AND SYNERGISTIC EFFECTS
Asthma and Other Respiratory Ailments Climate change
exacerbates the negative health effects of harmful air pollutants (e.g.,
particulate matter, ozone, sulfur dioxide, and nitrogen dioxide). While
increases in fine particulate matter (<2.5 microns—PM2.5) are a function of wildfires and the burning of fossil fuels, the latter is the predominate driver of anthropogenic climate change. In 2016, exposure
to ambient air pollution and/or household air pollution was estimated
to cause 7.1 million premature deaths worldwide per year, making it
the largest global environmental risk factor for reversible death and
disability (see Chap. 289 for an overview).
By increasing ground-level ozone and/or particulate matter concentrations in some regions, the higher temperatures associated
with climate change will directly increase the global burden and
severity of asthma (Chap. 287), the respiratory effects of allergies
(Chap. 352), rhinosinusitis, chronic obstructive pulmonary disease
(COPD), respiratory tract infections, interstitial lung disease, and
lung cancer, resulting in increased hospital admissions and premature
death. Figure 475-2 illustrates potential pathophysiologic mechanisms
by which this may occur.
Cardiovascular Disease Cardiovascular (CV) complications
of climate change share similar mechanisms with climate-sensitive
Cell barrier
damage
Ultrafine particles
Lung diseases
Asthma, COPD, Lung cancer,
Interstitial lung diseases,
Lung fibrosis, Acute lung injury
Innate
immunity
Adaptive
immunity
Oxidative
stress
Activated
T-cell MAPK
NFKB
AP-1
Ca2+
TNF-α
ROS
FIGURE 475-2 Mechanisms of ultrafine particle–induced respiratory health effects.
(Source: GD Leikauf et al: Mechanisms of ultrafine particle-induced respiratory
health effects. Exp Mol Med 52:329, 2020.)
3728 PART 17 Global Medicine
For clinicians, there are subtle management strategies to bear in
mind for climate-sensitive CV disease. For example, in new heartfailure patients, prescribers should be judicious about starting diuretics
(especially diuretic-ACE inhibitor combinations) before the summer
months or in areas with increased heatwaves in order to avoid exacerbating dehydration or heat-related illness. These patients may also
benefit from increasing potassium uptake. Figure 475-4 presents personal- and local-level interventions to reduce climate-sensitive disease
associated with air pollution.
Pregnancy Women exposed to high temperatures and air pollution
may be more likely to experience serious adverse pregnancy outcomes.
A systematic review of studies across diverse U.S. populations found a
statistically significant association of PM2.5, ozone, and heat exposure
with preterm birth, low birth weight at term, and stillbirth. As these
environmental exposures become more common with climate change,
an increased incidence of these complications is likely.
Potential pathophysiologic mechanisms for these outcomes are multifactorial: preterm birth may result from hematogenous transport of
inhaled PM2.5 and varied noxious chemicals and subsequent systemic
inflammation or perturbation of the autonomic nervous system; low
birth weight could be caused by the cumulative effect of alterations in
maternal cardiac, pulmonary, and renal function, placental inflammation, and direct exposure to oxidative stress; and stillbirth may involve
Adhesion
Molecules
↑ Inflammation
↑ Fibrinogen
Thrombosis
↑ Peroxynitrite
↑ NADPH Oxidase
↑ Superoxide + ↑ Nitric Oxide
eNOS
Uncoupling
Impaired EPC
Function
↑ ROS and RNS Low-grade Inflammation
Cardiometabolic Disease
↑ Proliferation
↑ Vasoconstriction
↓ Vasodilation
↑
Smooth Muscle
Proliferation ↑
Inflammatory
cytokine
Activated
Endothelium
Autonomic
Imbalance
Endothelial
Dysfunction
Direct Translocation Biologic Intermediates
Oxidative Stress
Air Pollution
CNS
Inflammation
HPA Axis
Activation
Neural
Reflex Arc
Systemic
Inflammation
Thrombotic
Pathways
Macrophage
NF-κB
↑
Platelet
Activation
TLR
↑
MMP-2
MMP-9 ↑
FIGURE 475-3 Biologic pathways whereby PM2.5 promotes cardiovascular events. (Reproduced with permission from S Rajagopalan: Air pollution and cardiovascular dsease
JACC state-of-the-art review. J Am Coll Cardiol 72:2054, 2018.)
3729Health Effects of Climate Change CHAPTER 475
derangements in oxygen transport, DNA damage, and direct placental
injury. Extreme heat events may lead to adverse pregnancy outcomes
through dehydration and subsequent alterations in thermoregulation,
blood viscosity, uterine blood flow, placental-fetal exchange, amniotic
fluid volume, and hormone release (e.g., prostaglandin or oxytocin).
These risks are disproportionately borne by black mothers. Thus,
failure to reduce air pollution to the WHO guideline level of 10 μg/m3
compounds structural racism.
■ HEAT-RELATED ILLNESSES
Renal Disease Various populations of agricultural workers who
labor in hot climates around the world have been noted to suffer
from chronic kidney disease (CKD), even those without common risk
factors such as diabetes mellitus, hypertension, glomerular disease,
or HIV. Although the cause has not been identified, potential mechanisms include genetic polymorphisms, nephrotoxicity secondary to
agrochemicals or heavy metals, and heat-associated injury (Fig. 475-5).
Heat Exhaustion and Heatstroke Please see Chap. 465 for an
overview of heat-related illnesses. These include heat cramps, heat
exhaustion, and heatstroke and can be expected to increase in incidence as temperatures rise. Certain communities suffer from significant peaks in average temperature resulting from the urban heat island
effect, which in the United States is related to policies such as redlining,
racial covenants, and strategic underinvestment in neighborhoods
segregated through such policies. Possible preventive measures include
developing clear heatwave strategies and establishing early warning
systems, mapping vulnerable populations, enhancing green space, and
providing cool-down zones. It is important that clinicians provide
guidance about heat-related illnesses prior to the start of summer
because waiting for heat warnings will not obviate risk. Medication
storage is an issue, especially for those that are carried by patients (e.g.,
epinephrine injections, naloxone, insulin). Evidence is not robust, but
there are some data to suggest that exposure to extreme heat (e.g., leaving an albuterol inhaler in a vehicle on a hot day) can impair delivery
mechanisms and/or degrade active ingredients of the medication itself.
■ NATURAL DISASTERS, COASTAL FLOODING,
AND DISPLACEMENT
Injury and Trauma While models predict fewer cyclones and
hurricanes in a warmer late-twenty-first-century climate, they do
forecast events of higher average intensity, precipitation, and the
number and occurrence days of very intense category 4 and 5 storms
(Fig. 475-6). Such natural disasters would be expected to result in
injuries and trauma seen in contemporary storms of high intensity
(albeit with higher frequency), but there are other ways climate change
will affect the incidence of physical trauma.
Studies have shown associations between anomalously warm temperatures and increased deaths from drownings (from people swimming
Shifting to clean fuels
Transportation reform
Reduce traffic emission(s)
Urban landscape reform
SOCIETAL AND GOVERNMENTAL INTERVENTIONS PERSONAL INTERVENTIONS
Emission trading programs
Redirection of science and
funding
Empowering civil society
Governmental and NGOled publicity
Face masks and air purifiers
Reduce in-traffic exposures
Reduce in-home
penetration of outdoor air
pollution
Lifestyle changes and
preventive medicine
• Exercise and healthy diet
• Preventive medications and screening programs
• Wearing face masks and installing air purifiers in homes
• Land-use assessment, minimum distances between sources and people, relocation of traffic
sources (including major trafficked roads), avoidance of mixed-use areas (industrial-residential)
• Switch coal-fired power plants to low-polluting renewable energy sources such as wind, tidal,
geothermal, and solar.
• Promote use of low-emission and zero-emission vehicles. Reduce sulfur content of motor fuels.
Restrict trucks from city centers, encourage active transport (walking and cycling).
• Diesel particle traps, catalytic converters, alternative fuels (natural gas, electric cars)
• Revenues raised through taxes can be directed to pollution control. Emissions trading programs
compensate companies who adhere to controls through credits that can be traded akin to
carbon credits
• Modifying priorities of climate change mitigation investments to a focus on near-term health
co-benefits. Focus on the imminent near-term danger of health effects of air pollution.
• Publicity and awareness campaigns through local data on air pollution within cities, counties
• Hard-hitting media campaigns akin to smoking on media to mitigate lobbying by industries
involved in power and automobiles
• Avoid commutes during rush hour
• Indoor air purifiers and closing windows; air conditioners
FIGURE 475-4 Social ecological interventions to reduce exposures or susceptibility to air pollution. (Reproduced with permission from S Rajagopalan: Air pollution and
cardiovascular disease JACC state-of-the-art review. J Am Coll Cardiol 72:2054, 2018.)
3730 PART 17 Global Medicine
Toxins and toxicants
Pesticides
Heavy metals
Silica
Other
Proximal tubular
uptake of toxin
from low renal
blood flow
Hyperosmolarity
(increased vasopressin
and aldose reductase)
Crystalluria
(urate) Rhabdomyolysis
Kidney inflammation and tubular injury
Heat exposure
Dehydration and extracellular volume loss
Primary organ
dysfunction
lncreased core
temperature
FIGURE 475-5 Possible mechanisms for the development of chronic kidney disease of unknown cause in agricultural communities. (From RJ Johnson et al: Chronic
Kidney Disease of Unknown Cause in Agricultural Communities. N Engl J Med 380:1843, 2019. Copyright © 2019 Massachusetts Medical Society. Reprinted with permission
from Massachusetts Medical Society.)
Present-day simulation
RCP4.5 late 21st century projection
Late 21st century minus present-day
0
45
30
15
0
–15
–30
–45
30 60 90 120 150 180 210 240 270 300 330 360
0
45
30
15
0
–15
–30
–45
30 60 90 120 150 180 210 240 270 300 330 360
0
45
A
B
C
30
15
0
–15
–30
–45
30 60 90 120 150 180 210 240 270 300 330 360
350
300
250
200
150
100
50
0
350
300
250
200
150
100
50
0
0
–20
20
40
60
80
100
120
–40
–60
–80
–100
–120
FIGURE 475-6 Simulated occurrence of all tropical storms (tropical cyclones with winds exceeding 17.5 m s−1) for (A) present-day or (B) late-twenty-first-century (RCP4.5; CMIP5
multimodel ensemble) conditions; unit: storms per decade. Simulated tropical cyclone tracks were obtained using the GFDL hurricane model to resimulate (at higher resolution)
the tropical cyclone cases originally obtained from the HiRAM C180 global mode. Occurrence refers to the number of days, over a 20-year period, in which a storm exceeding
17.5 m s−1 intensity was centered within the 10° × 10° grid region. (C) Difference in occurrence rate between late-twenty-first century and present day [(B) minus (A)]. White
regions are regions where no tropical storms occurred in the simulations [in (A) and (B)] or where the difference between the experiments is zero [in (C)]. (Source: TR Knutson
et al: Global projections of intense tropical cyclone activity for the late twenty-first century from dynamical downscaling of CMIP5/RCP4.5 scenarios. J Clim 28:7203, 2015 ©
American Meteorological Society. Used with permission.)
longer and more frequently), transportation accidents (driving performance worsens at higher temperatures and traffic increases), and
assaults (potentially from increased alcohol consumption and illicit
drug use). These deaths were partly offset by decreased falls, especially
among the elderly, in warmer years.
In addition, as more than half the world’s population lives within
60 km of the ocean, rising sea levels will destroy homes, medical infrastructure, and other essential services, including sewage treatment
systems and drinking water supplies. In concert with climate impacts
such as extreme heat and lack of freshwater, subsequent displacement
and migration will lead to increased mental illness, food insecurity, and
communicable disease.
Finally, extreme sudden-onset events can affect the availability
of medications through medical supply chain disruptions. Loss of
electricity during intense storms can also compromise vaccination
programs and the availability of needed medications. For example, in
3731Health Effects of Climate Change CHAPTER 475
Greenhouse gas
emissions (GHG)
Average
temperature &
weather
variability Air
humidity Precipitation
level
Precipitation
index
Soil
moisture
fertilizer
Climate/
weather
Food crop
yields
Child
undernutrion
Soil
quality
Labor capacity
Household
income
Food
affordability
Food prices
Utilization
rate
Household
access to
food
Per capita food
availability
consumption &
utilization
Mothers’ quality
of life
Rate of maternal
malnutrition
Rate of malnutritionrelated maternal
mortality
Malnourished
mothers
Evaporation
rate
Evapotranspiration
rate
Infectious
diseases
Health care
Rate of malnutritionrelated child mortality
Children’s quality
of life
Rate of child
malnutrition
FIGURE 475-7 Complex pathways from climate/weather variability to undernutrition in subsistence farming households. The factors involved in and the probable impacts
of weather variables on crop yields (blue arrows) and of food crop yields on undernutrition (red arrows). (Reproduced with permission from RK Phalkey et al: Climate change
impacts on childhood undernutrition. Proc Natl Acad Sci USA 112:E4522, 2015.)
2017 Hurricane Maria interrupted the production of essential drugs
and intravenous (IV) fluids manufactured in Puerto Rico, resulting in
nationwide shortages in the United States. Providers should ensure that
patients with electricity-dependent medical devices have a reasonable
contingency plan in case of power outages while noting that climaterelated displacements can interrupt patients’ access to medications for
chronic diseases and limit access to clinical care in general.
Mental Illness As of 2020, an estimated 80 million people (i.e.,
1% of humanity) were forcibly displaced from their homes, mainly
on account of violent conflict. It is expected that millions more will
be displaced in response to the effects of climate change. This has
ramifications for mental health (as do natural disasters) where resultant psychosocial stress can lead to an increased incidence of anxiety,
depression, and posttraumatic stress disorder (PTSD). Increased temperatures have also been found to be associated with higher rates of
suicide and domestic violence. Lastly, regarding clinical practice, many
psychoactive prescription drugs can interfere with thermoregulation;
their use therefore confers added risk during extreme heat events.
■ FOOD SECURITY AND OCEAN RESOURCES
Malnutrition Climate change threatens food and nutritional security through decreased crop yields in the setting of changes in precipitation, desertification, severe weather events, temperature extremes,
GHG emissions, ocean warming and acidification, coastal inundation
affecting dryland agriculture and aquaculture, and increasing competition from weeds and pests (Fig. 475-7). Livestock and fish production
are also projected to decline. For many, food will be less available, less
nutritious, and more expensive.
As chronic noncommunicable diseases, both undernutrition
(Chap. 334) and obesity (Chap. 401)—which affect approximately
2 billion people worldwide—share common drivers with climate
change. Current dietary practices (through land conversion and
overconsumption of ruminant meats) contribute to excess GHGs,
decreases in biodiversity, and depletion of water supplies. Variable
rainfall and increased flooding, which can contaminate freshwater
supplies, will make water security a defining challenge of this century.
Plant-based diets have the potential to decrease GHG emissions;
improve food security in LMICs; reduce mortality from stroke, type 2
diabetes mellitus, coronary heart disease, and cancer by 6–10%; and
reduce diet-related GHGs by 29–70% by 2050 compared with a reference diet (Fig. 475-8).
■ INFECTIONS AND DIARRHEAL DISEASE
(See Chap. 115)
POTENTIAL SOLUTIONS
Reductions in GHG emissions will require health professionals to voice
their evidence-based understandings of climate-sensitive pathologies
to lobby for political action. Other important systemic interventions
in health care include achieving universal health coverage (including
financial risk protection); equitable access to quality essential health
care services as well as safe, effective, and affordable medicines and
vaccines; making health care and health systems net-zero carbon; adding a climate-change lens to existing lines of research; improving data
quality and enhancing, standardizing, and integrating data collection
in LMICs and the tropics; and anticipating and correcting disasterrelated health care system failures, such as impacts to supply chains or
loss of electric power resulting from extreme weather events.
Interventions related to environmental policy include advocating
for a tighter particulate-matter air-quality standard, supporting institutional divestment from fossil fuels, and advocating for the rapid
drawdown of emissions and negative emissions strategies. Ecosocial
interventions, supported by national or global institutions, include
the distribution of clean cookstoves globally, switching to plant-based
diets, decreased air travel, reducing air conditioner use, and increased
3732 PART 17 Global Medicine
access to more public transportation. Finally, advocating for wealthredistribution schemes (e.g., reparations, progressive taxation, debt
cancellation, improved safety nets, underemployment insurance) to
empower disadvantaged populations to cope with climate hazards will
have positive ancillary effects on the social determinants of health,
the administration of health services, and the outcomes of clinical
interventions.
CONCLUSIONS
Without sweeping reductions in GHG emissions, over the next 50
to 100 years models predict increases in average global temperature
of 2–5°C (with localized highs), rising sea levels, and more frequent
and severe extreme-weather events, with resultant complications for
population health globally. The hostile consequences of climate change
will disproportionately affect vulnerable and marginalized groups, particularly those whose ability to cope with climate hazards is curtailed
by systemic racism, colonial legacies, illicit financial flows, and human
rights failings.
Health care professionals find themselves on the front line of the
climate crisis and remain, in many settings, sources of information and
counsel. In order to mitigate the impact of climate-sensitive diseases and
resulting health disparities, they must continue to extend their clinical
purview to environmental determinants and structural interventions.
■ FURTHER READING
Bekkar B et al: Association of air pollution and heat exposure with
preterm birth, low birth weight, and stillbirth in the US: A systematic
review. JAMA Netw Open 3:e208243, 2020.
Brief of Amici Curiae Public Health Experts, Public Health Organization, and Doctors In Support of Plaintiffs-Appellees’ Petition for
Hearing En Banc, Juliana v. United States of America, No. 18-36082
(9th Cir. Mar. 13, 2020).
Centers for Disease Control and Prevention: Climate Effects on
Health. Available from https://www.cdc.gov/climateandhealth/effects/
default.htm. Accessed June 12, 2020.
Hoffman JS et al: The effects of historical housing policies on resident
exposure to intra-urban heat: A study of 108 US urban areas. Climate
8:12, 2020.
The Lancet: Health and climate change. Available at https://www.
thelancet.com/climate-and-health. Accessed June 12, 2020.
The New England Journal of Medicine: Climate Crisis and
Health. Available from https://www.nejm.org/climate-crisis. Accessed
June 12, 2020.
Rajagopalan S et al: Air pollution and cardiovascular disease: JACC
state-of-the-art review. J Am Coll Cardiol 72:2054, 2018.
Raymond C et al: The emergence of heat and humidity too severe for
human tolerance. Sci Adv 6:eaaw1838, 2020.
Swinburn BA et al: The global syndemic of obesity, undernutrition,
and climate change: The Lancet Commission report. Lancet 393:791,
2019.
Government actions/public policy shifts Effects Impact on human health
Reduced risk of cardiovascular
disease, T2D, stroke,
cancer, obesity
Impact on nutrition
Improved food security
Preservation of protein and
micronutrient content of crops
Reduced greenhouse gases
Impact on climate change
Increased use of public transportation
Increased biking/walking
Reduced meat consumption
Shift to more plant-based diets
Establish sustainable dietary guidelines
Eliminate subsidies for commodity crops
Add cost of environmental degradation to
foods with high environmental footprint
Reduce demand for beef
Make improvements in urban design
Eliminate subsidies for fossil fuels
FIGURE 475-8 Strategies to mitigate the impact of climate change on human nutrition. (Republished with permission of Journal of Clinical Investigation from Climate
change and malnutrition: we need to act now, WH Dietz, 130:556,2020; permission conveyed through Copyright Clearance Center, Inc.)
Aging PART 18
Biology of Aging
Rafael de Cabo, David Le Couteur
476
■ AGING
The dramatic increase in the population of older people is one of the
most significant changes in human history. In the past few years, the
number of people over the age of 65 exceeded that of children under
the age of 5 for the first time, and by 2050, older people will likely outnumber children under the age of 14 (Fig. 476-1).
Old age is associated with an inexorable increase in the incidence of
chronic disease, multimorbidity, and mortality. In developed nations,
older people are living longer due to advances in medical care and
technology, but at the cost of longer periods of disability and the
iatrogenic burdens associated with intensive medical care of multiple
diseases, such as polypharmacy. Establishing the relationship between
aging and disease, particularly noncommunicable disease, is one of the
most important goals for biomedical research. Recent studies in animal
models have confirmed that the aging process is malleable, raising the
prospect that medical care in the future may treat aging itself rather
than multiple age-related diseases.
Aging is usually defined as a progressive process associated with
deterioration in structure and function, leading to increased susceptibility to disease and mortality, and is often associated with impaired
reproductive capacity. There are statistical, biological, and phenotypic components to aging. From the statistical perspective, aging in
humans is associated with an exponential risk of mortality with time
(Gompertz law of mortality). The biological mechanisms of aging are
encompassed by the “hallmarks of aging,” which describe the key cellular mechanisms underpinning aging. The phenotypic components
of aging include chronic diseases and age-related syndromes that are
often the target of medical interventions (Fig. 476-2).
A fundamental feature of aging is that for any quantitative factor
that can be measured in a population, the range of variability of values
for that factor increases with age.
■ EVOLUTIONARY THEORIES OF AGING
Evolutionary theories of aging attempt to explain why aging, which
impairs health and survival, has evolved, and why there is so much
variability in life span across taxa. Most theories are based on the
concept that in the wild, age-related mortality is secondary to extrinsic causes, such as predation, injury, and infection, and evolutionary
selection pressure is generated by early life survival and reproductive
success. Therefore, selection pressure to maintain health and extend
life beyond early reproductive years is minimal. In fact, traits may
evolve that are beneficial in early life and for reproduction but are
harmful if the animal lives to an older age. These theories were set out
by the classic “antagonistic pleiotropy” and “mutation accumulation”
theories of aging.
Aging is nonadaptive, meaning that it has not been shaped by evolution; it can be considered to be the consequence of evolutionary neglect
and is not usually considered to be genetically programmed. However,
many genes influence the aging process, and the initiating process
of aging most likely involves stochastic, nonprogrammed changes in
nuclear maintenance that influence gene expression and repair.
A common theme in the evolutionary theories of aging is that a
trade-off exists between aging and reproduction. Animals with high
extrinsic mortality tend to have short lives, small bodies, and greater
reproductive output, while animals with low extrinsic mortality, such
as humans and other primates, tend to have longer lives, larger bodies,
and fewer offspring. Moreover, some interventions that delay aging also
reduce reproductive potential. The disposable soma theory of aging
explicitly hypothesizes that evolution selects strategies that prioritize
utilization of finite resources to maintain germ cells necessary for
reproduction rather than the soma (non-germ cells), hence leading to
age-related accumulation of damage to the soma.
There are many exceptions to these theories in the animal kingdom
(Fig. 476-3). Some animals undergo “negligible senescence,” meaning
that no obvious biological changes of aging are noted and the rate of
mortality does not increase with time. These include some strains and
species of clams, sharks, hydra, and worms. The longest living vertebrate is the Greenland shark, which may live up to nearly 400 years. On
the other hand, a few animals undergo programmed aging and death.
These are the semelparous animals such as Pacific salmon and marsupial mice. In other animals, including humans, later life survival is
influenced by evolution through what is called the grandmother effect.
In these species, survival of offspring depends upon the care provided
by their long-lived grandmothers. This also explains the development
of an unusually long post-reproductive period of life in humans. Aging
remains a mystery. For every generalization, exceptions can be found.
For example, a mouse and a bat are very closely related genetically, but
the mouse lives about 2 years and a bat up to 25 years. Differences like
these are unexplained.
■ THE HALLMARKS OF AGING
Aging is associated with a range of molecular processes that are
remarkably similar between species. These hallmarks of aging are the
mechanistic pathways that are considered to be the underlying cause of
aging. The processes are highly interconnected, and impairment of one
process will impact the others (Fig. 476-2). Interventions that alter the
behavior of each of these pathways (via genetic manipulation, pharmacologic treatments, or nutritional interventions) influence aging and
life span of laboratory animals, such as mice, fruit flies (Drosophila
melanogaster), and worms (Caenorhabditis elegans). Each of the hallmarks is a potential target for pharmacotherapies that might delay
aging and the onset of age-related morbidity and increase both healthy
life span (health span) and total life span.
Genomic Instability The integrity of DNA is vulnerable to many
exogenous (e.g., irradiation, chemicals) and endogenous (e.g., oxidative stress) stressors that often generate random DNA lesions such as
point mutations, translocations, and chromosomal anomalies. A variety of mechanisms exist to repair these anomalies, but the mechanisms
are affected by genetic alterations in the repair machinery and by a
decrease in their efficiency with age. Mitochondrial DNA is especially
susceptible to damage with aging because of its proximity to free radicals produced during oxidative phosphorylation and the lack of histones and repair mechanisms in this organelle. Genetic manipulation of
0
1960 1980 2000 2020 2040
Year
Percentage of world population
Less than 5 years
65 years and older
5
10
15
20
FIGURE 476-1 Globally, the people over the age of 65 years now exceed children
under the age of 5 years.
3734 PART 18 Aging
Dementia
Cataracts
Heart disease
Sarcopenia
Cancer
Genomic
instability
Telomere
attrition
Epigenetic
alterations
Loss of
proteostasis
Dysregulated
nutrient sensing
Mitochondrial
dysfunction
Cellular
senescence
Stem cell
exhaustion
Intercellular
communication
Osteoporosis
Age
20 40 60 80 100
Risk of death
0.0
0.2
0.4
0.6
0.8
1.0
Survival
0.0
0.2
0.4
0.6
0.8
1.0
Risk of death
Survival
A B C
FIGURE 476-2 Definitions of aging include (A) a biological component, which is encapsulated by the nine hallmarks of aging, (B) a phenotypic component which includes
many chronic non-communicable diseases, and (C) a statistical component which in most species is an exponential (Gompertz) increase in the risk of mortality with age.
Ocean quahog clam Greenland shark
Negligible senescence
Antechinus Pacific salmon
Semelparous animals
Asian elephant Humans
Grandmother effect
FIGURE 476-3 Some species undergo negligible senescence while others, such
as the semelparous animals, undergo programmed aging and death. In some longlived species, including humans, there is a prolonged post-reproductive period
of life which may be secondary to the beneficial effects of grandmothers on the
survival of infants.
nuclear and mitochondrial DNA repair mechanisms shortens life span
in mice, while human premature aging syndromes are associated with deficiencies in genes necessary for nuclear maintenance. For example, Werner’s
syndrome is caused by mutations in a RecQ helicase gene (WRN) required
for repair of double-strand breaks, and Hutchinson-Guildford progeria syndrome is caused by mutations in the lamin A gene (LMNA)
required for structural support of the nucleus.
Telomere Attrition Telomeres are repeat sequences at the ends of
linear chromosomes that counteract the inability of DNA polymerase
to replicate the tips of chromosomes. In humans, telomeres consist
of a redundant TTAGGG sequence repeated several thousand times.
Some cells (e.g., germ cells, tumor cells) contain telomerase, which can
reform telomeres that are shortened during replication. In most cells,
after multiple divisions, the telomeres are truncated to a point where
cell division cannot continue. In cell culture, this number of divisions
is called the Hayflick limit, and cells that cannot undergo further division are said to have entered a phase of replicative cellular senescence.
Some studies in humans have found that telomere length in blood cells
decreases with age, while mice that have been genetically manipulated
to have short or long telomeres have decreased and increased life spans,
respectively.
Epigenetic Alterations Multiple systems regulate gene expression, such as DNA methylation, histone modification, and chromatin
remodeling. All of these processes change with age, leading to altered
transcription of genes, especially those involved with inflammation,
mitochondrial function, and autophagy pathways. The “epigenetic
clock” is a consistent age-related pattern of DNA methylation changes
in human blood samples that reflect chronologic age. Histones are
proteins that package DNA into nucleosomes to influence DNA
availability for transcription. The sirtuins are a family of nicotinamide
adenine dinucleotide (NAD)–dependent enzymes that regulate histones through deacetylation, thus eliciting beneficial effects on aging
and life span. For example, overexpression of sirtuins and their activation by drugs such as resveratrol increase life span in model organisms.
Loss of Proteostasis Damaged proteins in cells are removed by
the autophagy-lysosomal system and the ubiquitin-proteosome system. These processes are impaired with aging, which can lead to the
formation of intracellular and extracellular aggregates of damaged
proteins and other cellular components, such as lipofuscin, Lewy
bodies, neurofibrillary tangles, and amylin (Fig. 476-4). Both caloric
restriction and inhibition of mechanistic target of rapamycin (mTOR)
can activate autophagy and delay aging. Autophagy is also necessary for
the removal of damaged mitochondria (mitophagy), and age-related
impairment of mitophagy contributes to syndromes such as sarcopenia
and frailty.
Deregulated Nutrient Sensing Nutrition has a profound effect
on aging in all species. One of the most important nutritional interventions that influences aging is caloric restriction (CR). CR involves
providing animals with less food (usually ~30–50% less than what
is given to controls fed ad libitum). Long-term CR extends life span
while delaying the onset of many age-related pathologies and diseases.
Several interconnected pathways mediate the effects of nutrition and
CR on aging and age-related conditions through downstream effectors
(Fig. 476-5), and drugs have been developed that act on these pathways
3735Biology of Aging CHAPTER 476
Lipofuscin Lewy Bodies
Neurofibrillary tangles Amylin
FIGURE 476-4 Impaired proteostasis with old age contributes to the accumulation
of lipofuscin in the liver, Lewy bodies in the substantia nigra, neurofibrillary tangles
in neurones and amylin in beta islet cells.
Insulin/IGF-1 FGF21 SIRT1 AMPK MTOR
Dietary Energy Dietary Macronutrients
Nucleus
regulation
transcription
ATG FOXO PGC1A S6K
Autophagosome
autophagy
proteostasis
Cytoplasm
metabolism of fats
and carbohydrates
Endoplasmic reticulum
protein synthesis
Nutrient Sensing Pathways
Key Downstream Proteins
Cellular Compartments and Functions Influenced by Diet and Aging
Mitochondria
ATP synthesis
FIGURE 476-5 Nutrient sensing pathways. The main molecular switches that respond to changes in dietary intake (red boxes: Insulin/IGF1, MTOR, AMPK, SIRT1, FGF21)
influence a range of downstream effectors (some of these are shown in the grey boxes). These regulate key cellular processes (green boxes), such as metabolism of fat and
carbohydrates (CHO), autophagy, mitochondria, and protein synthesis. CHO, carbohydrate.
to replicate some of the effects of CR. These so-called “CR mimetics”
have been shown to increase life span regardless of calorie intake.
These key nutrient-sensing pathways include the following:
1. Insulin and insulin-like growth factor (IGF)-1 signaling pathway.
Animals with genetic downregulation of this pathway have a longer
life span, and this includes the very long-living Methuselah mice
with knock out of the growth hormone (GH) receptor. Humans
with GH receptor deficiency (Laron syndrome) have less cancer and
diabetes. Many of the downstream effectors belong to the FOXO
(forkhead box O) family of transcription factors, with genetic variation in some FOXO genes being associated with human longevity.
2. mTOR pathway. This pathway is activated by amino acids and the
insulin/IGF-1 signaling pathway and, therefore, can be manipulated by dietary protein intake. Inactivation of mTOR by dietary
restriction or rapamycin is associated with reduced protein synthesis
and increased autophagy, leading to increased life span.
3. Sirtuins. The sirtuin family of NAD+-dependent deacetylases
encompasses seven members in mammals that are activated in
response to low energy supply. Sirtuins regulate gene expression
via histone deacetylation and mitochondrial biogenesis. Increased
sirtuin activity induced by genetic manipulation, CR mimetics, or
NAD supplementation has been associated with increased life span.
4. Adenosine monophosphate (AMP)–activated protein kinase
(AMPK). Dietary energy restriction is associated with high levels of
AMP in cells, which triggers the activation of AMPK. Observational
studies in humans have suggested that metformin impacts agerelated conditions. Human clinical trials of metformin are planned
to determine its effects on aging.
5. Fibroblast growth factor 21 (FGF21). Dietary protein restriction
increases the production and release of FGF21 into the blood, with
a subsequent increase in AMPK signaling and insulin sensitivity.
Overexpression of FGF21 increases life span in mice.
Mitochondrial Dysfunction Age-related changes in mitochondria include increased electron leakage with a subsequent decrease
in ATP production, primarily due to impaired complex IV activity.
Accumulation of mitochondrial DNA damage and swollen mitochondria with disrupted cristae results in impaired mitochondrial function, which leads to increased generation of superoxide radicals and
hydrogen peroxide. Human mitochondria DNA frequently develops
a truncation at a typical site that gives the aberrant mitochondria a
proliferative advantage, and they become the predominant type of
mitochondria in aging cells. As a consequence, age-associated oxidative damage to fat, proteins, and DNA occurs, forming the basis of
the free radical theory of aging. Antioxidants have been investigated
as an antiaging intervention but to no avail. Many of the nutritional
and pharmacologic interventions that delay aging are associated with
increased mitochondrial biogenesis mostly via upregulation or activation of the transcriptional coactivator PGC1α.
Cellular Senescence Senescent cells have stopped dividing as a
result of either telomere shortening or other damage mediated by the
INK4/ARF system. Senescent cells (sometimes called zombie cells)
accumulate in various tissues with increasing age. They produce a wide
range of inflammatory cytokines collectively called the senescenceassociated secretory phenotype (SASP). SASP contributes to systemic
inflammation. Genetic manipulation aimed at eliminating senescent
cells that express INK4 and pharmacologic interventions with drugs
3736 PART 18 Aging
that eradicate senescent cells (called senolytics; e.g., dasatinib, quercetin, fisetin) delay the progression of age-related pathologies.
Stem Cell Exhaustion The age-associated reduction in the number of stem cells is probably due to replicative senescence and telomere
shortening. Transplantation of pluripotent stem cells from young
donors to old recipients extends life span in mice and may improve
frailty in humans. Another strategy involves induction of genes that
regulate stem cells (Yamanaka factors: OCT4, SOX2, KLF4, MYC),
which delays aging in progeria mouse models.
Altered Intracellular Communication and Inflammation
Aging is associated with low-grade activation of the innate immune
system, leading to elevated circulating levels of interleukin (IL) 6,
tumor necrosis factor-α (TNF-α), and other molecules such as Creactive protein and elevation of erythrocyte sedimentation rate. This
change in intracellular communication, called inflammaging, may be
secondary to several factors including SASP, chronic infection with
cytomegalovirus, obesity, leaky gut, and activation of the nuclear
factor-κB (NF-κB) pathway. Inflammation is a key factor in the pathogenesis of many chronic diseases and, in particular, frailty.
■ GEROSCIENCE AND THE RELATIONSHIP
BETWEEN AGING AND DISEASE
An unequivocal relationship exists between aging and disease, and old
age is the major risk factor for most chronic diseases. The nature of
the relationship has been the source of debate for millennia. On one
hand, it has been argued that aging is similar to any other disease and,
therefore, is amenable to therapeutic interventions. On the other hand,
it has been argued that aging is an inevitable and untreatable process
that increases the risk for diseases. Regardless, a marked and often
exponential increase in the prevalence and incidence of most chronic
diseases occurs with age, and the main burden on noncommunicable
diseases is carried by older people. The burden of disease is usually
captured by units called disability-adjusted life-years (DALYs), which
quantify both years of life lost (compared to remaining life expectancy)
and years lived with disability. DALYs emphasize the impact of disease
on younger people because of their greater remaining life expectancy.
Even so, DALYs increase dramatically beyond age 60, particularly for
cardiovascular, neurologic, and cancer-related conditions (Fig. 476-6).
In addition, several conditions are generally considered to be primarily
age-related disorders, including dementia, sarcopenia, frailty, and osteoporosis. These conditions are very rare below the age of 50.
Geroscience refers to the study of the relationship between aging
biology and disease. Aging leads to impairment of many physiologic
systems that will increase susceptibility to disease. For example, aging
is associated with marked changes in immune function. Immunosenescence refers to age-related deterioration of the responsiveness of the
immune system to infection and other antigenic challenges caused by
(1) thymic involution with reduced naïve T cells and impaired memory
T cells, (2) a reduction in hematopoietic stem cells, and (3) impaired
function of antigen-presenting cells. Aging is associated with many
endocrine changes, most notably a reduction in sex steroids and growth
hormone, which contribute to sarcopenia and osteoporosis. Vascular
changes, including increased arterial stiffness that leads to high peripheral vascular resistance and microvascular pathology, have an obvious
link with cardiovascular disease, but also probably contribute to other
conditions such as dementia, osteoarthritis, and sarcopenia.
Although the usual dogma is that aging is a process that increases
susceptibility to diseases, the relationship between chronic disease
and aging may be much more fundamental. The pathogenesis of most
chronic diseases includes one or more of the hallmarks of aging, and
differences between disease and normal aging are defined by a quantitative difference in the expression of these hallmarks and the tissues
that are affected. Likewise, the difference between aging and disease
in terms of the clinical features is often based on quantitative differences. Therefore, a continuum exists between aging and many chronic
diseases. These are often separated by so-called “pre-diseases” or “subclinical diseases,” which are evidence of this continuum. Therefore,
chronic disease can be considered to be a manifestation of aging that
is predominant in a particular tissue. The presence of several chronic
diseases, termed multimorbidity, represents aging-associated changes
that are more advanced in several tissues. Frailty can be defined as a
multisystem aging syndrome, where aging-related changes are present
in most tissues, leading to multiple deficits and impaired function.
Aging is the main risk factor for chronic disease, and chronic diseases can be considered to be a manifestation of the biological changes
of aging. Therefore, treatments that target aging may not only delay
aging and increase life span but also reduce or delay chronic diseases.
The “longevity dividend” refers to the concept whereby an intervention
that impacts the aging process can delay the onset of a wide range of
age-related diseases and syndromes.
■ STRATEGIES THAT INCREASE HEALTH SPAN AND
DELAY AGING
Aging is an intrinsic feature of human life whose manipulation has fascinated humans ever since becoming conscious of their existence. Several long-term experimental interventions (e.g., resveratrol, rapamycin,
spermidine, and metformin) may open doors for pharmacologic
Age group (years)
0–4 5–14 15–29 30–49 50–59 60–69 70+
Disability adjusted life years
0
20
40
60
80 Ischemic heart disease
Stroke
COPD
Dementia
Lung cancer
FIGURE 476-6 The relationship between age and disability adjusted life years for several common non-communicable diseases. COPD, chronic obstructive pulmonary
disease.
3737Biology of Aging CHAPTER 476
strategies. Surprisingly, most of the effective aging interventions proposed to date converge on only a few molecular pathways: nutrient
signaling, mitochondrial proteostasis, and the autophagic machinery.
Life span is inevitably accompanied by a gradual functional decline,
steady increase of several chronic diseases, and ultimately death. For
millennia, it has been a dream of mankind to prolong both life span
and health span. Developed countries have profited from advances in
medical care and technology, improvements in their public health care
systems, and better living conditions derived from their socioeconomic
power to achieve remarkable increases in life expectancy during the
last century. In the United States, the percentage of the population
aged ≥65 years is projected to increase from 13% in 2010 to 19.3% in
2030. However, old age remains the leading risk factor for major lifethreatening disorders. The number of people suffering from age-related
diseases is anticipated to almost double over the next two decades. The
prevalence of age-related pathologies represents a major threat and an
economic burden that urgently needs effective interventions.
Molecules, drugs, and other interventions that might decelerate
aging processes continue to be a major focus among the general public
and scientists of all biological and medical fields. Over the past two
decades, this interest has taken root because many of the molecular
mechanisms underlying aging are interconnected and linked with
pathways that cause diseases, including cancer, cardiovascular disease,
and neurodegenerative disorders. Unfortunately, results often lack
reproducibility because of the unavoidable problem of the time needed
to assess the effectiveness of antiaging interventions in mammals.
Experiments lasting the lifetime of animal models are prone to develop
artifacts, increasing the possibilities and time windows for experimental discrepancies. Some inconsistencies in the field arise from overinterpreting the results of animal models with shortened life span and
scenarios of accelerated aging.
Molecules, drugs, and other interventions have been proposed to
have antiaging properties throughout history and into the present. In
the following sections, interventions will be restricted to those that
meet the following highly selective criteria: (1) promotion of life span
and/or health span, (2) validation in at least three model organisms,
and (3) confirmation by at least three different laboratories. These
include (1) caloric restriction (CR) and intermittent fasting regimens,
(2) some pharmacotherapies (resveratrol, rapamycin, spermidine, and
metformin), and (3) exercise.
Caloric Restriction One of the most important and robust interventions that delays aging is CR. This outcome has been recorded in
rodents, dogs, worms, flies, yeasts, monkeys, and prokaryotes. CR is
defined as a reduction in the total caloric intake, usually of ~30%, and
without malnutrition. CR reduces the nutrient-mediated release of
growth factors, such as growth hormone, insulin, and IGF-1, which
have been shown to accelerate aging and enhance the probability for
mortality in many organisms. Yet, the effects of CR on aging were first
discovered by McCay in 1935, long before the discovery and signaling
properties of these hormones and growth factors. Some of the pathways that mediate this remarkable response of CR have been elucidated
in experimental models. These include the nutrient-sensing pathways
(mTOR, AMPK, insulin/IGF-1, and sirtuins) and the family of FOXO
transcription factors (orthologs are found in D. melanogaster and C.
elegans). The transcription factor Nrf2 appears to confer most of the
anticancer properties of CR in mice, even though it is dispensable for
life span extension.
The effects of CR in monkeys have been assessed in two studies
with different outcomes: one study observed prolonged life, while the
other did not. In these monkey studies, key differences were noted
in the onset of the intervention, diet composition, feeding protocols,
and genetic background that may explain this discordance. However,
both studies confirmed that CR increases health span by reducing the
risk for diabetes, cardiovascular disease, and cancer. In humans, CR
is associated with extended life span and increased health span. This
is most convincingly demonstrated in Okinawa, Japan, where one of
the most long-lived human populations resides. In comparison to the
rest of the Japanese population, Okinawan people usually combine
an above-average amount of daily exercise with a below-average food
intake. However, when Okinawan families moved to Brazil, they
adopted a Western lifestyle that affected both exercise and nutrition,
causing a rise in weight and a reduction in life expectancy by nearly
two decades. In the Biosphere II project, volunteers lived together for
24 months undergoing an unforeseen severe CR that led to improvements in insulin, blood sugar, glycated hemoglobin, cholesterol levels,
and blood pressure—all outcomes that would be expected to benefit
life span. CR changes many aspects of human aging that might influence life span such as the transcriptome, hormonal status (especially
IGF-1 and thyroid hormones), oxidative stress, inflammation, mitochondrial function, glucose homeostasis, and cardiometabolic risk
factors. Epigenetic modifications are also an emerging target for CR.
Periodic Fasting It must be noted that maintaining CR while
avoiding malnutrition over a long period of time is not only arduous
in humans but is also linked with substantial side effects. For instance,
prolonged reduction of calorie intake may decrease fertility and libido,
impair wound healing, reduce the potential to combat infections, and
lead to amenorrhea and osteoporosis. How can CR be translated to
humans in a socially and medically acceptable way? A whole series
of periodic fasting regimens are asserting themselves as suitable
strategies, among them (1) the alternate-day fasting diet, (2) the “5:2”
intermittent fasting diet, (3) a 48-h fast once or twice each month, and
(4) daily time-restricted feeding (TRF). Periodic fasting is psychologically more viable, lacks some of the negative side effects of CR, and
is only accompanied by minimal weight loss. All these dietary interventions involve a substantial reduction of caloric intake for a defined
period of time, leading to an elevation of circulating ketone bodies
during those low-calorie intake periods, illustrating the metabolic
switch from the utilization of glucose as a fuel source to the use of fatty
acids and ketone bodies. This metabolic shift results in a reduction in
the respiratory exchange ratio (the ratio of carbon dioxide produced to
oxygen consumed), indicating greater metabolic flexibility and energy
production efficiency from use of fatty acids and ketone bodies.
It is striking that many cultures implement periodic fasting rituals,
including Buddhists, Christians, Hindus, Jews, Muslims, and some
African animistic religions. It could be speculated that a selective
advantage of fasting versus nonfasting populations is conferred by
health-promoting attributes of religious routines that periodically limit
caloric intake. Indeed, several lines of evidence indicate that intermittent fasting regimens exert antiaging effects. For example, improved
morbidity and longevity were observed among Spanish nursing home
residents who underwent alternate-day fasting. Rats subjected to
alternate-day fasting live up to 83% longer than control animals fed ad
libitum, and even one 24-h fasting period every 4 days is sufficient to
generate life span extension.
Repeated fasting and eating cycles may circumvent the negative
side effects of sustained CR. This strategy may even yield health benefits despite overeating behavior during the nonfasting periods. In
a landmark experiment, mice fed a high-fat diet in a time-restricted
manner, i.e., with regular fasting breaks, showed reduced inflammation markers, did not develop fatty liver, and were slim in comparison
to mice fed ad libitum despite equivalent total calories consumed.
From an evolutionary point of view, this kind of feeding pattern may
reflect mammalian adaptation to food availability: overeating in times
of nutrient availability (e.g., after a hunting success) and starvation in
times of food scarcity. This is how some indigenous peoples who have
avoided Western lifestyles live today; those who have been investigated
show limited signs of age-induced diseases such as cancer, neurodegeneration, diabetes, cardiovascular disease, and hypertension.
Fasting exerts beneficial effects on health span by minimizing the
risk of developing age-related diseases, including hypertension, neurodegeneration, cancer, and cardiovascular disease. The most effective
and rapid repercussion of fasting is a reduction in hypertension. Two
weeks of water-only fasting resulted in blood pressure <120/80 mmHg
in 82% of subjects with borderline hypertension. Ten days of fasting
cured all hypertensive patients who had been taking antihypertensive
medication previously.
3738 PART 18 Aging
Periodic fasting dampens the consequences of many age-related
neurodegenerative diseases in mouse models of Alzheimer’s disease,
Parkinson’s disease, Huntington’s disease, and frontotemporal dementia, but not amyotrophic lateral sclerosis. Fasting cycles are as effective
as chemotherapy against certain tumors in mice. When combined
with chemotherapy, fasting protects mice against the negative side
effects of chemotherapeutic drugs, while enhancing efficacy against
tumors. Combining fasting and chemotherapy rendered 20–60% of
mice cancer-free when inoculated with highly aggressive tumors such
as glioblastoma or pancreatic tumors, which have 100% mortality even
with chemotherapy.
Pharmacologic Interventions to Delay Aging and Increase
Life Span Virtually all obese people know that stable weight reduction will lower their risk of cardiometabolic disease and enhance their
overall survival, and yet only 20% of overweight individuals are able to
lose 10% of weight for a period of at least 1 year. Even in the most motivated people (such as the “Cronies” who deliberately attempt long-term
CR in order to extend their lives), long-term CR is extremely difficult
to adhere to. Thus, much focus has been directed at the possibility of
developing medicines that replicate the beneficial effects of CR, but
without the need for reducing food intake (“CR mimetics”; Fig. 476-7).
RESVERATROL Resveratrol, an agonist of SIRT1, is a polyphenol that
is found in grapes and red wine. The potential of resveratrol to promote
life span was first identified in yeast, and it has gathered fame since, at
least in part, because it has been suggested to be responsible for the socalled French paradox whereby wine reduces some of the cardiometabolic risks of a high-fat diet. Resveratrol has been reported to increase
life span in many lower order species such as yeast, fruit flies, worms,
and fish, as well as mice on high-fat diets. In monkeys fed a diet high
in sugar and fat, resveratrol had beneficial outcomes related to inflammation and cardiometabolic parameters. Some studies in humans have
also shown improvements in cardiometabolic function, while others
have not. Gene expression studies in animals and humans reveal that
resveratrol mimics some of the metabolic and gene expression changes
of CR. In most experimental models, resveratrol induces beneficial
health effects by suppressing inflammation, oxidative damage, tumorigenesis, and immunomodulatory activities. Resveratrol also leads
to improvements in mitochondrial function and protection against
obesity, cancer, and cardiovascular dysfunction.
RAPAMYCIN Rapamycin, an inhibitor of mTOR, was originally discovered on Easter Island (Rapa Nui, hence its name) as a bacterial
secretion with antibiotic properties. Before its emergence in the
antiaging arena, rapamycin was known as an immunosuppressant
and cancer chemotherapeutic agent in humans. Rapamycin extends
life span in all organisms tested so far, including yeast, flies, worms,
and mice. However, the potential utility of rapamycin in life span
extension in humans is likely to be limited by adverse effects related
to immunosuppression, impaired wound healing, proteinuria, and
hypercholesterolemia, among others. An alternative strategy may be
the implementation of intermittent rapamycin treatment, which was
found to increase mouse life span.
SPERMIDINE Spermidine is a physiologic polyamine that induces
autophagy-mediated life span extension in yeast, flies, and worms.
Endogenous spermidine levels decrease during life of virtually all
organisms including humans, with the remarkable exception of centenarians. Oral administration of spermidine or upregulation of bacterial
polyamine production in the gut leads to life span extension in shortlived mouse models. The life span effects of spermidine are mediated
through the inhibition of histone acetylases and the activation of
autophagy genes, such as atg7, atg11, and atg15. Spermidine has also
been found to have beneficial effects on neurodegeneration and cardioprotection through activation of autophagy. Spermidine supplementation is safe in humans and has been associated with positive effects on
cognitive function of older adults and on blood pressure maintenance.
METFORMIN Metformin, a biguanide first isolated from the French
lilac, is widely used for the treatment of type 2 diabetes. Metformin
decreases hepatic gluconeogenesis and increases insulin sensitivity.
Other actions of metformin include AMPK activation, leading to
mTOR inhibition and lower mitochondrial complex I activity, and
activation of the transcription factor SKN-1/Nrf2. Metformin increases
life span in different mouse strains including female mice predisposed
to high incidence of mammary tumors. At a biochemical level, metformin supplementation is associated with reduced oxidative damage
and inflammation and mimics some of the gene expression changes
seen with CR. Based on experimental data on the positive outcomes in
model organisms and the evidence emerging from epidemiologic studies, a clinical trial known as TAME (Targeting Aging with Metformin)
has been initiated to assess whether metformin can delay the onset of
age-related diseases beyond its effects on glucose metabolism. TAME
is planning to enroll 3000 subjects, aged 65-–79, in a multicenter trial
in the United States.
Exercise and Physical Activity In humans and animals, regular
exercise reduces the risk of morbidity and mortality. Given the marked
increase in cardiovascular disease in the older people, the effects of
exercise on human health may be even stronger than those seen in
laboratory mice, as mice do not develop atherosclerosis and have a far
lower incidence of age-related cardiovascular disease. An increase in
aerobic exercise capacity, which declines during aging, is associated
with favorable effects on blood pressure, lipids, glucose tolerance, bone
density, and depression in older people. Likewise, exercise training
protects against aging disorders such as cardiovascular disease, diabetes mellitus, and osteoporosis. Exercise is the only intervention that
can prevent or even reverse sarcopenia (age-related muscle wasting).
Even moderate or low levels of exercise (30 min of walking per day)
have significant protective effects in obese subjects. In older people,
regular physical activity has been found to increase the length of stay
in independent living.
While clearly promoting health and quality of life, regular exercise
does not extend life span. Furthermore, the combination of exercise
with CR has no additive effect on maximal life span in rodents. On
the other hand, alternate-day fasting with exercise is more beneficial
for muscle mass than either treatment alone. In nonobese humans,
exercise combined with CR has synergistic effects on insulin sensitivity
and inflammation. From the evolutionary perspective, the responses to
hunger and exercise are linked: when food is scarce, increased activity
is required to hunt and gather.
Hormesis Paradoxically, the term hormesis describes the protective
effects conferred by the exposure to low doses of stressors or toxins
(or as Nietzsche stated, “What does not kill me makes me stronger”).
Adaptive stress responses elicited by noxious agents (chemical, thermal, or radioactive) precondition an organism, rendering it resistant
to subsequent higher and otherwise lethal doses of the same trigger.
HO
OH
Resveratrol Rapamycin
Spermidine Metformin
NH NH
NH2 NH2 H2N
H
N
OH
HO
O
O O
O
OO
O
HO O
N
O O
OH
N
H
N
FIGURE 476-7 Chemical structure of four agents (resveratrol, rapamycin,
spermidine, and metformin) that have been shown to delay aging in experimental
animal models.
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