Editor’s Headnote
I invite you to take a look at the background and credentials enumerated for Dr. Kenneth Edwin Schmader on the Duke University School of Medicine website (here). I guarantee that you will be impressed, as you should be. This guy’s the real deal. All I’ll add here is that I first met Ken in the fall of 1972 when we got randomly assigned to the same freshman hall in college. We’ve been best friends, from my perspective, ever since. Ken combines kindness, wit, and intellect in spectacular ways. I’ve got to tell you as well that he’s the best point-guard I’ve ever played with. You get open—and the ball appears in your hands. You need some backside help on defense—and the Schmade is there. Well, Ken is helping me out once more by generously writing the very first Guest Rant for my Substack. I could not be more grateful. So let’s hear now what Dr. Schmader wishes we all knew more about.
I really wish people know more about Geroscience
by Dr. Kenneth E. Schmader
Definition
The biological hallmarks of aging are the molecular and cellular events that bring about the aging process and together determine aging characteristics. Geroscience is an interdisciplinary field that aims to understand how this aging process is related to age-related conditions, disability, and disease.
Qualifications
I am a Geriatrician and clinical investigator, Professor of Medicine, past Chief of Geriatrics at Duke University Medical Center and Director of the Geriatric Research, Education and Clinical Center (GRECC), Durham VA Health Care System. I direct a National Institute on Aging funded center of excellence at Duke, called the Pepper Older Americans Independence Center, where we study aging processes in the context of understanding and optimizing physical resilience in older adults.
Why do the hallmarks of aging and Geroscience matter?
An older women came to our Geriatrics clinic with concerns about feeling tired, feeling unsteady on her feet, back and joint pains, difficulty hearing, and having less mental “sharpness.” She noted she was not able to bounce back from injuries and infections like she used to. Her past medical history included osteoarthritis, hypertension, hypothyroidism, hearing loss, breast cancer (in remission). She was independent but having more difficulty with completing some of her activities of daily living. She noted that she gets up in the morning feeling OK, then looks in the mirror and thinks, “is that me? I look so old – how did I get this way?”
That surprise that you have grown older than you realize is all too common. We all age. We know that biological aging, also known as senescence, starts in the third decade of life. We know the rate of aging varies widely among individuals. As this women’s story illustrates, aging is associated with conditions and diseases that affect quality of life and threaten independence. Importantly, she asks the fundamental question as to how did this happen? What exactly underlies the aging process? What is it about the aging process that is a driver of chronic disease and conditions, disability and loss of resilience?
Humankind has wondered about this question for as long as we have been alive. Gerontology, the formal study of aging, began in the early 20th century. However, it is only within the past several years that, due to phenomenal advances in molecular biology and computing power, remarkable leaps are occurring in better understanding the fundamental biological processes behind aging. These advances have led to the emergence of a field called geroscience.
Geroscience
Geroscience seeks to understand the molecular and cellular mechanisms that underlie the aging process and make aging a major risk factor for common chronic conditions and diseases of older people. A central tenet is that slowing the rate of aging will improve health. Aging is by far the largest risk factor for many chronic diseases and disability. Therefore, geroscience seeks to provide innovative interventions to prolong independence, reduce the burden of age-related disease, and increase resilience to major stressors. Essentially the idea is to target the biology of aging to prevent, delay, or cure diseases associated with aging.
Investigators world-wide are engaged in geroscience. In the United States, the National Institute on Aging (NIA) is a major thought leader and funder of this effort. The NIA recently established a Geroscience Special Interest Group that pulls all the NIH institutes and centers together to discover the basic biology at the intersection among aging, chronic disease, frailty, and resilience.
Most people have not heard of Geroscience. The reason it’s important to be aware of this revolutionary transformation in thinking is that discoveries in the biology of aging are leading to the development of compounds, known as gerotherapeutics, that may slow aging and delay the onset and progression of not just one disease but multiple chronic diseases. These interventions may increase healthy years of life (healthspan) in individuals and populations, with the potential to revolutionize not just the health of older adults but also health across the life span.
Biological Hallmarks of Aging
In the most recent summation of the literature, the authors identified 12 biological hallmarks of aging, which are far too many to discuss in detail here. (Hallmarks of aging: An expanding universe - PubMed (nih.gov)) For our purposes, let’s review two well established hallmarks for which there are clinical intervention trials in progress in people.
1) Cellular senescence (how cells themselves become old and lose the ability to grow and divide)
What is this?
The cell cycle is the process through which cells replicate and make new cells. The process is a series of events that includes interphase, during which the cell grows and prepares for cell division, and mitosis, when the cell completes its division. Cellular senescence is defined as a stable arrest of the cell cycle so it no longer divides or proliferates. The cells no longer divide but they are not dead.
Why is this a problem?
Normally, the senescent cells are cleared and replaced by progenitor cells. With aging, the capacity to replace cells is exhausted or becomes inefficient. The result is the eventual accumulation of senescent cells in multiple tissues and cell types. The senescent cells are not biologically inert. They release proteins that cause inflammation and cell damage that contribute to aging, referred to as the ‘‘senescence-associated secretory phenotype.’’ The accumulation of tissue-specific senescent cells occurs in many diseases, including Alzheimer’s disease, Parkinson’s disease, diabetes, and atherosclerosis.
What are some potential solutions to the problem?
The elimination of senescent cells by drug or genetic interventions extends the healthspan and longevity of naturally aged mice and is therapeutic in many diseases in mouse models. These findings have prompted the search for compounds that selectively remove senescent cells, otherwise known as ‘‘senolytics.’’ Senolytic therapeutic strategies have been studied in animal models and are now in several human clinical trials. Examples of senolytic drugs under investigation include dasatinib, quercetin, fisetin, curcumin, and rapamycin. Dasatinib plus quercetin are under study for use in pulmonary fibrosis, Alzheimer’s disease, diabetic chronic kidney disease, and osteoporosis. Fisetin is under study for use in osteoarthritis, frailty, and complications due to COVID-19.
2) Mitochondrial dysfunction (Impairment of energy production)
What is this?
Mitochondria are specialized structures within the cell that power the cells and tissues of the body. The mitochondria's central purpose is to produce energy. Different tissues have different amounts of mitochondria. Muscle, brain, liver, and kidney have a lot of mitochondria.
Why is this a problem?
If there are defects in functioning of mitochondria, there will be reduced energy and impairments in the functioning of cells. This in turn may affect the ability of organs to function, especially when under stress, and contribute to that feeling of less energy and tiredness when we get older. With aging, mitochondrial function deteriorates due to multiple intertwined mechanisms. The function of mitochondria is fundamental for the maintenance of health. Its ongoing deterioration is a key factor in aging characteristics.
What are some potential solutions to the problem?
The improvement of mitochondrial function and bioenergetics has been demonstrated in mouse models for several compounds, including, for example elamipretide, polyphenols (in cocoa), and carnitine in pilot studies in humans. These findings have prompted larger more definitive clinical trials using agents shown to target mitochondrial dysfunction. These agents include polyphenols, resveratrol, metformin, rapamycin, carnitine, and mitochondrially-targeted coenzyme Q (MitoQ) or mitochondrially-targeted vitamin E (MitoVitE).
How might people use senolytic or bioenergetic therapies to improve their healthspan if they are shown to work in definitive clinical trials?
It may be in the form of a pill or combination of pills. For example, in one pilot clinical trial, a dasatinib pill and quercetin pill were taken by mouth over three consecutive days each week. Fisetin was also taken as a pill by mouth daily. Elamipretide and carnitine are used in a similar fashion. In addition, accumulating evidence in humans supports the use of non-drug interventions such as exercise and diet that have been repeatedly shown to slow biological aging. The hope is that these drug and non-drug gerotherapeutics can be assimilated into routine patient care.
These hallmarks of aging are presented as distinct entities but they also interact, influence, and relate to each other. Similarly, many compounds target not just one hallmark but several hallmarks at the same time and can have multiple positive effects. Clearly this is a complex area where discoveries will continue to unfold. Keep your eye out for the results of the trials and how they may affect clinical practice and our lives. Here’s a great place to explore this exciting new way of thinking made possible by amazingly creative investigators and phenomenal advances in scientific technologies and computing: Trans-NIH Geroscience Interest Group (GSIG) | National Institute on Aging
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