Conference Probes Essence of Aging, Frailty, and Disease

BY NIH CATALYST STAFF

A gray-bearded Marshall Allen, leader of the legendary jazz ensemble called The Sun Ra Arkestra, jaunted onto the stage at The Birchmere in Alexandria, Virginia recently, looking like a kid in his 70s. He then proceeded to wail on the alto sax for 90 minutes — focused and inventive, rising with ease, turning and pointing to his band of a dozen-plus musicians, always in command.

Remarkable is the fact that Allen is not in his 70s. He is 99.

What is the secret of Allen’s longevity? The occupation of jazzman tends not to produce many nonagenarians. Toots Thielemans had a good run to 94, albeit on a less-strenuous instrument, the chromatic harmonica. Swing jazz drummer Viola Smith died in 2020 just shy of her 108th birthday. But examples of others are fewer than notes on a toy xylophone.

Perhaps Marshall Allen is a so-called super-ager? A super-ager is someone who ages more slowly than most people and thus is less affected by frailty and chronic disease compared to others in their 80s or 90s.

Just a few weeks after Allen’s local concert, scientists gathered for the fourth NIH Geroscience Summit, April 24–26, at the Natcher Conference Center on the NIH Bethesda campus. A discussion of super-agers, like Allen, was one of the many topics on the agenda.

The summit built on previous gatherings held in 2013, 2016, and 2019. A decade since that first summit, scientists are narrowing in on some startling revelations about the nature of aging.

The ageless pursuit of understanding aging

The Buddha, Siddhartha Gautama, described aging as one of the three universal characteristics of existence and taught the importance of developing an understanding of impermanence and cultivating a mindset of acceptance. Aristotle observed that aging seemed to be influenced by lifestyle and family heredity and not solely determined by the passage of time.

Geroscience furthers our exploration of the concept and realities of aging, a science with philosophical undertones.

“There is no consensus definition of geroscience, but it can be understood as the search for ways to translate knowledge of molecular and cellular mechanisms of aging into ways to improve health at older ages,” said Ronald Kohanski, Director of the Division of Aging Biology (DAB) at the National Institute on Aging (NIA) and organizer of the summit.

“Geroscience was founded upon an observation that age is the major risk factor for many diseases and the general decline of function over time,” Kohanski told the Catalyst. “Age as the passage of time is not modifiable, [however] we know from basic research in the biology of aging that many aging traits may be reversed or accelerated, clearly indicating that aging is modifiable.”

The term geroscience was popularized by Felipe Sierra, a past director of DAB who retired in 2020. Sierra has described geroscience as distinct from basic aging research in several ways. Whereas biology of aging research typically focuses on understanding the molecular and cellular mechanisms underlying the aging process—changes in gene expression and metabolism, for example—geroscience is a more interdisciplinary field that aims to apply insights from basic and behavioral research to delay the onset of age-related disease and to improve human healthspan and lifespan.

Strategies involve identifying new targets for drug development, exploring the potential of lifestyle interventions such as exercise and diet, or investigating the role of stem cells in aging and disease. As such, geroscience has a more translational focus than basic aging research in its quest for practical interventions to improve human health.

Sierra and Kohanski created the trans-NIH Geroscience Interest Group (GSIG) in 2012 as a platform to explore this integrative concept. In little over a decade, geroscience has become a mature, international field of research, as evidenced in part by the changing of the name of the journal Age; Journal of the American Aging Association to GeroScience in 2014.

Some of the notable advances in geroscience research at and funded by the NIA include:

• Identification of aging biomarkers such as epigenetic changes, gene- and protein-expression patterns, and changes in the microbiome
• Development of senolytic therapies such as drugs that target rare cells that secrete inflammatory factors and accumulate with age
• Revelation of the role of inflammation in aging
• Advancements in genetic engineering to study the effects of specific genetic mutations on aging and age-related diseases
• Identification of interventions that can extend lifespan in animal models and that may improve health at older ages, including caloric restriction

The first geroscience summit helped produce the geroscience hypothesis that slowing the rate of aging will improve health at older ages by delaying the onset of disease and reducing severity when diseases arise at older ages.

This fourth summit was “both retrospective and prospective,” Kohanski said, in addressing how to leverage new technologies in a clinical setting while pushing the basic science to the next level.

Is prolonged aging extending suffering?

The fourth geroscience summit theme was “Geroscience for the Next Generation,” a nod to younger investigators taking more interest in aging research. Divided nearly evenly over nine sessions and three seven-hour days — all archived at videocast.nih.gov — the summit brought together dozens of scientific presenters from diverse backgrounds, including several from the NIH intramural research program.

The first session, not addressed in previous summits, was on health disparities. Speakers included two NIH institute directors: Eliseo J. Pérez-Stable, Director of the National Institute of Minority Health and Health Disparities (NIMHD), and Shannon Zenk, Director of the National Institute of Nursing Research (NINR).

The session explored what may be obvious, that health disparities affect health negatively. Less understood, however, is the effect of disparities on the aging process and how these disparities affect an individual’s health over their life course.

As seen in the broader field of geroscience, the data can seem contradictory. For example:

• Some in traditionally marginalized minority populations with poor access to health care living remarkably long, healthy lives—clues to their longevity might lie in high levels of physical activity or the emerging scientific explication of resilience, according to panel discussants
• Centenarians, who generally exemplify exceptional aging
• Certain non-industrialized Indigenous populations living traditional lifestyles, largely free of chronic disease of aging
• Younger populations with diseases such as cancer or HIV in which aging appears to be accelerated, likely as a result of chronic inflammation, among other causes

In the second session, Sofiya Milman, Associate Professor in the Department of Medicine at Albert Einstein College of Medicine (New York), set the tone with a slide that revealed that the true burden of aging is many years of declining health. The onset of chronic disease, on average, extends from approximately age 50 to age 85.

Life expectancy in the United States is 78 years, which is ranked 46th among nations; the highest is Japan at 85 years, according to the WHO.

Milman said she and her colleagues are focused on a target to delay the onset of poorer health to a five-year range around age 80 and compress that 30-year span to just five years. A more ambitious goal is to delay the onset of chronic disease until age 90, population wide.

“This is a very realistic, biologically plausible concept,” Milman said. “And that is because we do have people among us—people who live very long lives, centenarians and super-centenarians—who don’t only live to age 100 and beyond but also maintain their health almost the entirety of their lives.”

Milman presented data revealing how most centenarians, compared with people with average lifespans, delay the onset of morbidity by up to 30 years. How? 

Research points to strong genetic factors: poorly defined “longevity genes,” many related to hormonal pathways. One biological pathway involves signaling via growth hormone and insulin-like growth factor-I, Milman said. Diminished signaling via this pathway appears to delay aging, resulting in longer healthspan in both animal models and humans.

To better understand the protective genetic variants that promote healthy aging, Milman and colleagues launched the SuperAgers Family Study in November 2022 with the goal of recruiting 10,000 people aged 95 or older with no significant cognitive impairment, like aforementioned jazzman Marshall Allen.

Luigi Ferrucci, NIA Scientific Director and Senior Investigator in the NIA Longitudinal Studies Section, explained the global increase in life expectancy over the last 180 years: from age 45 to about age 85. But with that came an increase in the years with disability.

“The problem is that this incredible success in [prolonging life expectancy] comes with taxes," Ferrucci said. That tax includes extending illness and disability during that longer lifetime.

One problem appears to be that disease begets disease. Males over age 70 with a single chronic disease have a 20% chance of developing a second disease. If they have two diseases, they have a 23% chance of developing a third. If they have three diseases, they have a 31% chance of developing a fourth. And if they have four diseases, they have a 51% chance of developing a fifth.

This is multimorbidity, which is the co-occurrence of two or more chronic conditions so common among the elderly, and geriatric syndromes, a catch-all category crudely summed up in the expression “it sure does suck getting old.”

Geriatrics traditionally treats diseases as they develop. But geroscience may lead to an era of proactive geriatric medicine, Ferrucci said.

“Imagine you can affect the process that leads to disease instead of treating the disease,” Ferrucci told the Catalyst. “That would be a complete revolution in health care. You can make the best healthcare in the world, but if you are only mitigating the disease that is already there, you only expand the period that people live with this disease; you never expand the period of life that is characterized by [good] health and the enjoyment of life. Geroscience is the promise that this will be possible.”

Mathematics of aging

Summit speakers also explored the mathematics of aging: methods for measuring good health and modeling declining health. The progress in development of biomarkers was presented by Nathan Basisty, an investigator and NIH Distinguished Scholar in the NIA Translational Geroproteomics Unit.

Stratification biomarkers hold great promise in this regard, Basisty said, directing the audience to the work of Stephen Kritchevsky, a professor of gerontology and geriatric medicine at Wake Forest University School of Medicine (Winston-Salem, North Carolina).

Stratification biomarkers can include a variety of measures—epigenetic marks, telomere length, circulating proteins, and metabolites—that change with age and can be used to estimate biological age. Such biomarkers can help target interventions and treatments to those who are most likely to benefit. 

NIH Intramural's Role

“Intramural research at NIH plays a critical role in advancing geroscience,” Kohanski said, naming just a few contributions to date: 

• The NIA Translational Gerontology Branch, led by Senior Investigator Rafael de Cabo, develops methods and interventions that support healthy aging and prevent or delay the onset of functional decline and age-related disease
• The Baltimore Longitudinal Study of Aging (BLSA) examines heterogeneity in human health and function with age
• The IRP-led Study of Longitudinal Aging in Mice serves as a comparative animal model counterpart to the BLSA

Summit organizers noted that there is no universally accepted meaning among clinicians for the concept of geroscience. This hinders the creation of clinical trials and thus the direct clinical applications of geroscience. As such, we have yet to capitalize on geroscience as a clinically helpful tool for predicting health outcomes, preventing disease, enhancing resilience, and treating geriatric syndromes.

All three days of the summit are archived individually at https://videocast.nih.gov. The third day’s recording, at https://videocast.nih.gov/watch=49460, concludes with a nice overview of the entire summit—in case you are worried about aging too much while watching the entire event.