Key Points
Introduction: The Geroscience Hypothesis
Geroscience as a Multidisciplinary Approach
Disease Drivers of Aging: Why Cancer, HIV, and Diabetes?
The Geroscience Hypothesis: What We Know—and What We Don't
Telomeres and Chronic Disease: A Two-Way Street
Stress and HIV: A Bidirectional Relationship
Clinical Implications for Patients
Limitations and Open Questions
Recommendations for Patients and Researchers
Frequently Asked Questions
Source Information

Key Points

Chronic diseases such as cancer, HIV, and diabetes may accelerate biological aging through mechanisms like telomere shortening and inflammation.
Some treatments, including chemotherapy and antiretroviral therapy, may speed up telomere attrition, while statins and metformin may protect it.
The Diabetes Prevention Program showed lifestyle intervention had a powerful effect in preventing diabetes in people over 60.
Depression and anxiety are linked to shorter telomeres, and in HIV, depression is associated with higher mortality.
A mouse study found an immunotherapy was lethal to older mice but helped younger ones, showing age affects treatment safety.

Introduction: The Geroscience Hypothesis

For decades, scientists have known that aging contributes to the development and progression of many chronic diseases. But far less research has examined the inverse relationship: do chronic diseases and their treatments actually accelerate the aging process? This question was the central focus of the Second Geroscience Summit, held on April 13–14, 2016, in New York City. The summit brought together experts from leading institutions, including the National Institute on Aging (NIA), the American Federation for Aging Research, the Genetics Society of America, and the New York Academy of Sciences. The organizing principle was the geroscience hypothesis: the idea that aging is the major modifiable risk factor for most chronic diseases. By targeting the fundamental biological drivers of aging, researchers hope to combat not just one disease but multiple chronic diseases simultaneously. The conventional view has long treated aging as a nonmodifiable risk factor. That has changed recently, thanks to the recognition among aging biologists of a limited number of "pillars" that appear to drive the aging process. These pillars were identified through research based on three classic tenets of aging biology: caloric restriction, cell senescence, and free radicals. While these initial theories have evolved, they have allowed researchers to begin translating findings into pharmacological approaches aimed at these pillars. The epidemiological evidence is clear: early exposure to severe diseases and/or their treatments leads to an acceleration of aging, defined by an increased and premature risk of developing age-related diseases and conditions. The summit's goal was to dig deeper and identify the molecular and cellular mechanisms responsible for these observations—with a particular emphasis on how diseases and their treatments interact with the major pillars of aging.

Geroscience as a Multidisciplinary Approach

Dr. Richard J. Hodes from the National Institute on Aging explained how geroscience is woven throughout the NIH's organizational structure. The NIA's extramural program is organized around four divisions, each uniquely positioned to advance this field:

Division of Aging Biology: Leads geroscience at the NIA, focusing on the basic biochemical, genetic, and physiological mechanisms underlying aging and age-related changes
Division of Neuroscience: Studies the dementias of old age and the normally aging brain, intersecting with geroscience in areas of disease mechanisms and age-related brain changes
Division of Behavioral and Social Research: Explores aging at individual and societal levels, including the biological mediators of social stressors
Division of Geriatrics and Clinical Gerontology: Supports research on health and disease in the aged, with a focus on aging-related diseases

The NIH comprises 27 different institutes and centers, and nearly all of them investigate diseases for which aging is a risk factor. Aging-related changes affect bodily functions at every level, from cellular metabolism and inflammatory responses to proteostasis (the maintenance of protein balance) and epigenetic modifications. These changes are collectively known as the "pillars of geroscience." To raise awareness of aging biology's role in disease, the NIA joined with 20 other NIH institutes to form the Geroscience Interest Group (GSIG). The GSIG organized the first Geroscience Summit in October 2013, which resulted in papers, a book, and multi-institute funding opportunities. The second summit, reported in this article, followed in April 2016.

Key Findings Highlighted by Hodes

One of the most significant NIA-supported findings came from the Diabetes Prevention Program studies, led by the National Institute of Diabetes and Digestive and Kidney Diseases. The results showed a particularly profound effect of lifestyle intervention in preventing diabetes in individuals over 60 years old, relative to the same intervention in younger participants. Another striking finding came from a 2013 study by Bouchlaka and colleagues. A systemic cancer immunotherapy strategy was 100% lethal to older mice after just 48 hours, while all of the younger animals survived and were actually helped by the therapy. This demonstrates the life-saving importance of preclinical testing of therapies in older animals—treatments that work in young bodies may be dangerous in aging ones. Dr. Hodes also highlighted innovative research showing that removal of senescent cells (cells that have stopped dividing) from aging mice through genetic strategies results in enhanced structure and function of muscle and other tissues. These findings in model systems provide a basis for translation into clinical studies.

Disease Drivers of Aging: Why Cancer, HIV, and Diabetes?

Dr. Felipe Sierra of the NIA explained that while aging is recognized as a major risk factor for most chronic diseases, there is still widespread perception that aging is immutable. As a result, both research and clinical trials often focus on curing or preventing specific diseases rather than addressing aging itself. The first Geroscience Summit in October 2013 identified seven major pillars of aging, but the door was left open for additional pillars not yet identified. One such underexplored pillar: the appearance of early major diseases and their treatment, which epidemiological studies show can lead to premature or accelerated appearance of age-specific traits, including chronic morbidity. Three diseases were chosen for focused discussion at the 2016 summit:

HIV/AIDS
Diabetes
Cancer

Why these three? The choice was driven by the need to narrow the scope of discussion, but the issues raised are expected to apply, with modifications, to all or most diseases that leave lasting effects (sequelae) affecting later susceptibility to age-related conditions. The summit addressed both the effects of the diseases themselves and the effects of their treatments. An important acknowledgment: people of advanced age are rarely affected by a single chronic disease; they often experience multiple comorbidities. However, the focus was on early disease appearance in relatively young people. In those cases, cancer, HIV/AIDS, and diabetes are often found alone, and the initial disease is treated vigorously. This has led to important increases in survival—but comorbidities appear later as patients age, reducing health span, the portion of life spent in good health.

The Geroscience Hypothesis: What We Know—and What We Don't

Dr. Steven N. Austad from the University of Alabama at Birmingham opened with a powerful observation: aging occurs even in the absence of disease. This is demonstrated by the steady decline in performance of the world's best master athletes as they grow older. Yet aging is intimately associated with virtually all fatal diseases of modern life, because it increases vulnerability to disease and compromises the ability to recover. Dr. Austad emphasized that nonfatal maladies of aging deserve attention too. Chronic joint pain, loss of vision and hearing, and muscle weakness have become especially important in recent times. The biomedical community has become successful at delaying death, as shown by steadily rising life expectancy for well over a century. But it has not been successful at delaying aging itself. Consequently, the number of people needing joint replacement for chronic pain, cataract surgery for low vision, or assistance with daily living activities has steadily risen. These chronic fatal and nonfatal maladies have become the number one threat to human health globally.

Three Critical Unanswered Questions

Despite successes in extending the life of laboratory animals through genetic, dietary, and pharmaceutical interventions—which have revealed key players like insulin/IGF and mTOR signaling in complex molecular networks underlying longevity—Dr. Austad identified three critical questions that remain unanswered:

Do life-extending interventions extend health, or do they simply delay death? This is perhaps the most important question for translation into human therapies. Extending the unhealthy period of life near its end is not a goal worth pursuing. Recently, assessment of age-related health trajectories has become a major focus of laboratory longevity studies.
Will life-extending interventions work outside the laboratory? Lab animals are protected from infectious diseases, poor diets, and unpredictable environmental events. Some interventions, such as dietary restriction, appear to compromise resistance to at least some infectious diseases—a substantial consideration in the real world.
Will effects observed in short-lived species translate to longer-lived species like humans? Only a fraction of cancer treatments successful in mice have proven therapeutically viable in humans. Similarly, very few Alzheimer's disease therapies have translated from success in mice to success in humans.

Dr. Austad's conclusion was direct: "There is no way to determine whether this will be true for known interventions in mouse aging without performing the human trials." He noted that such trials, involving older participants, would not need to be excessively lengthy to detect whether health is extended. "Multiple drug candidates have already been identified. It is time for the first clinical trial of putative senescence-retarding therapies."

Telomeres and Chronic Disease: A Two-Way Street

Dr. Elissa Epel from the University of California, San Francisco, unpacked the role of telomeres—the protective caps on the ends of chromosomes—in the relationship between chronic disease and aging.

What Are Telomeres and Why Do They Matter?

Telomeres are a window into one type of aging: replicative senescence, the inability of dividing cells to continue dividing, and thus the inability of tissue to replenish itself. The most common measure in human studies is the average telomere length in blood, across all immune cells. Telomere shortness is an early risk factor for immune senescence. When telomeres reach a critical shortness, the cell enters either senescence or apoptosis (programmed cell death). The intracellular enzyme telomerase can promote telomere lengthening, preventing the age-related shortening that comes with cell division.

Telomeres Predict Disease in Humans

Damage to telomeres—or the inability to rebuild telomere length after cell division—is thought to be a very common pathway to cell senescence in humans, partly because humans are so long-lived. In lower species, this is less important. Rodents, for example, start with very long telomeres and live shorter lives, so telomere attrition only matters in extreme cases, such as genetic knockouts. Telomere length is useful in human research because it is:

Easy to measure in population-based studies
Predictive of early onset of diseases of aging, as shown by many meta-analyses
A signal that other likely aspects of cell aging may be present

Short telomeres are bidirectionally related to other aspects of aging biology. Dysfunctional telomeres impair mitochondria and lead to systemic inflammation. Telomeres also play a direct mechanistic role in aging, as demonstrated by Mendelian randomization studies—a research method that uses genetic variants to examine causal effects.

Disease Processes May Shorten Telomeres

Robust evidence now shows that telomere shortness precedes the onset of cardiovascular disease and diabetes. Early telomere attrition creates risk for early diseases of aging. But once a chronic disease develops, many aspects of the disease process can promote accelerated telomere attrition. A common triad underlies many diseases of aging:

Oxidative stress
Inflammation
Hyperglycemia/insulin resistance

Diabetes offers a clear example of this vicious cycle. Once a person has diabetes, impaired beta-cell function and resulting higher levels of these biochemical stressors can further shorten telomeres. Psychiatric diseases follow a similar pattern. The presence of psychiatric disease is associated with shorter telomeres, particularly for major depression and anxiety disorders. There are dose–response relationships: the longer the duration of depression, the shorter the telomere length. Longitudinal studies are needed to determine the strength of causal directions, but given the high comorbidity of medical and psychiatric conditions, it's important to consider that depression itself may alter aging biology—not just physical disease.

Disease Treatments Can Speed Up or Slow Down Telomere Attrition

Treatments for diseases may further affect the rate of telomere attrition—either speeding it up or slowing it down:

Statins and possibly metformin may prevent telomere attrition
Highly active antiretroviral therapy (ART) in HIV appears to accelerate telomere attrition
Chemotherapy can damage telomeres of both cancerous cells and healthy cells

Dr. Epel summarized the situation: while cell aging predicts disease, once disease is present, both disease processes and aspects of treatment can further affect telomere stability and repair, and thus the rate of attrition over time. She added a practical suggestion: "There is a tremendous amount that could be easily learned by incorporating assessments of cellular aging, such as telomere length, into treatment studies."

Stress and HIV: A Bidirectional Relationship

Dr. Gretchen N. Neigh from Virginia Commonwealth University presented on the relationship between stress and HIV infection. Individuals living with HIV face a high stressor burden, which includes:

External stressors: financial burden and stigma
Internal stressors: the presence of the virus itself and the effects of antiretroviral medication

Evidence of this burden is visible in the increased incidence of stress-related disorders among individuals living with HIV, such as depression and posttraumatic stress disorder (PTSD). The combination matters for survival: one report demonstrated that women living with both depression and HIV have higher mortality than euthymic (normally mooded) women living with HIV. Dr. Neigh explained the relationship between stress and stressors using an analogy: stress is like a rubber band being stretched. An organism's response to a stressor is the physiological state of stress, and stress is designed to return the organism to homeostasis—the internal balance the body constantly works to maintain. Initially, the relationship between stressors and stress is completely predictable and reversible. The force (stressor) is applied, and the stress response returns the system to homeostasis; the relationship is elastic, or resilient. However, if the stressors are too great or too prolonged, the system's elasticity can be overwhelmed, leading to lasting damage. [The original article text continues beyond this point, but the provided excerpt ends here.]

Clinical Implications for Patients

This research carries several important messages for patients: 1. Aging is not immutable. The geroscience hypothesis holds that reducing the rate of aging could delay or slow the appearance and progression of not one but most age-related chronic ailments at once—including life-threatening diseases such as cancer, vascular disease, and diabetes, as well as chronic conditions like arthritis, osteoporosis, and mild cognitive impairment, and age-related syndromes like frailty, loss of resilience, and fatiguability. 2. Early disease shapes later health. Exposure to serious diseases and/or their treatments can accelerate the appearance of age-related diseases and conditions later in life. Patients who survive cancer, HIV, or diabetes in early or mid-life may need closer monitoring for age-related conditions. 3. Treatments themselves affect cellular aging. Chemotherapy can damage telomeres of healthy cells, and antiretroviral therapy may accelerate telomere attrition—while statins and metformin may protect telomeres. These are important considerations in shared treatment decisions with healthcare providers. 4. Mental health is physical health. Depression and anxiety are linked to shorter telomeres, and in the case of HIV, depression is associated with higher mortality. Treating mental health conditions may be an important component of slowing biological aging. 5. Age matters for treatment safety. The Bouchlaka mouse study—in which an immunotherapy was 100% lethal to older mice within 48 hours but helped younger mice—underscores the importance of testing treatments in older populations and being cautious about generalizing results from younger to older patients. 6. Lifestyle interventions work. The Diabetes Prevention Program showed a particularly profound effect of lifestyle intervention in preventing diabetes in individuals over 60, compared with younger participants.

Limitations and Open Questions

The summit discussions acknowledged important limitations:

The three diseases discussed (cancer, HIV/AIDS, and diabetes) were chosen to narrow the scope; the issues raised are expected to apply with modifications to most diseases that leave lasting effects influencing later disease susceptibility
There is no agreed-upon definition or measure for the "rate of aging," which remains a colloquial concept
It remains unknown whether life-extending interventions extend health span or simply delay death
Interventions that work in protected laboratory environments may not translate to real-world conditions; dietary restriction, for instance, appears to compromise resistance to at least some infectious diseases
Only a fraction of interventions successful in mice translate to humans, as shown by the track record in cancer and Alzheimer's disease research
Longitudinal studies are needed to determine the strength of causal directions between telomere shortening and psychiatric conditions
Few studies have directly examined the effects of medications on telomere attrition
People of advanced age are rarely affected by a single chronic disease; multiple comorbidities are the norm, and the summit's focused approach may not capture the full complexity of real-world patient situations

Recommendations for Patients and Researchers

For researchers:

Incorporate assessments of cellular aging, such as telomere length, into treatment studies
Initiate the first clinical trials of putative senescence-retarding therapies—as Dr. Austad stated, "It is time"
Conduct preclinical testing of therapies in older animal models before human trials, as the Bouchlaka study demonstrated the dangers of assuming age does not matter
Investigate the molecular and cellular mechanisms linking early disease and its treatment to accelerated aging
Explore the intersection between the pillars of aging and the disease processes of cancer, HIV, and diabetes to identify therapeutic targets

For patients:

Know that lifestyle interventions are powerful—the Diabetes Prevention Program demonstrated profound benefits of lifestyle change in people over 60
Manage chronic conditions carefully; uncontrolled disease (like diabetes) can create a cycle of oxidative stress, inflammation, and further cellular aging
Take mental health seriously—depression and anxiety are linked to accelerated cellular aging, and treating them may have physical benefits
Have informed conversations with healthcare providers about the long-term cellular effects of treatments like chemotherapy and long-term antiretroviral therapy
Discuss remaining healthy lifespan ("health span") goals with your care team, not just disease treatment

Frequently Asked Questions

Can chronic diseases like cancer, HIV, or diabetes actually speed up the aging process?

Yes, growing evidence suggests that early exposure to serious diseases and their treatments can accelerate biological aging. This may happen through mechanisms overlapping with core aging pillars, including cellular senescence, telomere shortening, inflammation, and oxidative stress. This can lead to premature age-related conditions, so survivors may need closer monitoring later in life.

Do treatments for chronic diseases affect how fast my cells age?

Some treatments may affect cellular aging. Chemotherapy can damage telomeres in healthy cells, and antiretroviral therapy for HIV appears to accelerate telomere attrition. In contrast, statins and possibly metformin may help prevent telomere shortening. Discuss these potential long-term effects with your healthcare provider when making treatment decisions.

Can lifestyle changes really help prevent diabetes, especially in people over 60?

Yes. The Diabetes Prevention Program studies showed a particularly profound effect of lifestyle intervention in preventing diabetes in individuals over 60 years old, compared with younger participants. This suggests that healthy lifestyle changes are powerful at older ages and can offset some effects of aging and disease risk.

What are telomeres and why are they important for aging?

Telomeres are protective caps on the ends of chromosomes. Each time cells divide, telomeres shorten. When they become critically short, cells enter senescence or die. Short telomeres are an early risk factor for immune senescence and predict early onset of aging-related diseases such as cardiovascular disease and diabetes.

Can depression or anxiety affect physical aging?

Research suggests they can. Presence of psychiatric disease, particularly major depression and anxiety disorders, is associated with shorter telomeres. Longer duration of depression is linked to even shorter telomeres. In women with HIV, having both depression and HIV was associated with higher mortality than HIV alone, highlighting that mental health matters for physical health.

Why might a treatment that works in younger people be risky for older people?

A 2013 study in mice showed that a cancer immunotherapy was 100% lethal to older mice within 48 hours, while all younger animals survived and were actually helped. This demonstrates the importance of testing treatments in older populations and being cautious about applying results from younger people to older patients.

Is aging itself considered a modifiable risk factor for chronic diseases?

The geroscience hypothesis proposes that aging is the major modifiable risk factor for most chronic diseases. By targeting fundamental biological drivers of aging, researchers hope to combat multiple chronic diseases at once, not just one. This represents a shift from viewing aging as unchangeable to potentially delaying age-related ailments.

I have cancer, HIV, or diabetes. Could these diseases or their treatments speed up aging, and should I get a second opinion about my treatment plan?

Yes, chronic diseases like cancer, HIV, and diabetes may accelerate biological aging through mechanisms such as telomere shortening and inflammation. Some treatments, including chemotherapy and antiretroviral therapy, may speed up telomere attrition, while statins and metformin may protect it. Because treatments can affect cellular aging, a second opinion can help you weigh the long-term effects of your treatment options. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original Article: "Disease drivers of aging"

Authors: Richard J. Hodes, Felipe Sierra, Steven N. Austad, Elissa Epel, Gretchen N. Neigh, Kristine M. Erlandson, Marissa J. Schafer, Nathan K. LeBrasseur, Christopher Wiley, Judith Campisi, Mary E. Sehl, Rosario Scalia, Satoru Eguchi, Balakuntalam S. Kasinath, Jeffrey B. Halter, Harvey Jay Cohen, Wendy Demark-Wahnefried, Tim A. Ahles, Nir Barzilai, Arti Hurria, and Peter W. Hunt

Publication: Annals of the New York Academy of Sciences (Ann N Y Acad Sci), December 2016, Volume 1386(1), pages 45–68. Published online: doi:10.1111/nyas.13299

Original Publication Context: This article reports proceedings from the Second Geroscience Summit, held April 13–14, 2016, in New York City, co-organized by the trans-NIH Geroscience Interest Group, the American Federation for Aging Research, the Genetics Society of America, and the New York Academy of Sciences.

Note: This patient-friendly article is based on peer-reviewed research published in the Annals of the New York Academy of Sciences. The original article text provided was partially truncated at the end of the HIV/stress section; content covering that section reflects only the portions available. The authors declared no conflicts of interest.

Can Chronic Diseases Speed Up Aging? What the Second Geroscience Summit Reveals

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