{"id":3404,"date":"2022-05-16T19:41:49","date_gmt":"2022-05-16T19:41:49","guid":{"rendered":"https:\/\/medschool.prd.vanderbilt.edu\/vanderbilt-medicine\/?p=3404"},"modified":"2022-05-16T19:41:49","modified_gmt":"2022-05-16T19:41:49","slug":"the-science-of-longevity","status":"publish","type":"post","link":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/the-science-of-longevity\/","title":{"rendered":"The Science of Longevity"},"content":{"rendered":"
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Photo by Erin O. Smith<\/figcaption><\/figure>\n

When someone asks her age, Abrie Pillow says that she\u2019s 10.<\/p>\n

\u201cI\u2019m 82, but I put the eight and two together as a joke,\u201d she laughs.<\/p>\n

Pillow is energetic and busy, with gardening and other projects at home, church and community volunteer work, family gatherings and great grandchildren sleepovers. She and her husband, Joe Nickerson, 85, are aging well, she says.<\/p>\n

She attributes her own longevity to always being mindful of what she eats, maintaining a healthy weight, staying physically and mentally active, and devoting her time and energy to others. She keeps her husband busy too.<\/p>\n

\u201cI haven\u2019t convinced her yet that I\u2019m retired,\u201d Nickerson quips.<\/p>\n

They also have genetics on their side. Pillow\u2019s mother died last year at age 101; her father lived into his 70s. Nickerson\u2019s parents lived to 90 and 95.<\/p>\n

Pillow and Nickerson are doing what\u2019s recommended for maintaining good health in general: eating healthy foods, exercising and staying socially engaged. The prescription is the same for living a long life.<\/p>\n

To age well, \u201cright now, environmentally, all we can control is our diet and our exercise,\u201d says Laura Niedernhofer, MD\u201998, PhD\u201996, director of the Institute on the Biology of Aging and Metabolism at the University of Minnesota and an alumna of Vanderbilt University School of Medicine.<\/p>\n

But medications that target aging to put off disease and extend our health span \u2014 the number of years we live in good health (not necessarily an extension of overall life span) \u2014 may be on the horizon. That\u2019s the aim of investigators pursuing the \u201cgeroscience hypothesis,\u201d the idea that aging itself is the greatest risk factor, by far, for most chronic diseases.<\/p>\n

\u201cDoesn\u2019t it make sense to therapeutically target something about the biology of aging, instead of risk factors like blood pressure and cholesterol?\u201d Niedernhofer asks. \u201cWe could be very impactful and reduce the risk of many diseases at the same time if we could target the biology of aging.\u201d<\/p>\n

The need is acute. The U.S. Census Bureau calls 2030 a \u201cdemographic turning point\u201d when all baby boomers will be 65 or older, and by 2034, the Census Bureau projects that older adults will outnumber children for the first time in U.S. history. By 2060, nearly one in four Americans will be 65 or older, up from about one in six in 2020.<\/p>\n

\u201cOur society is going to change, and aging, as a broad field, needs input from people with every angle of expertise \u2026 from ethics to governance to policy to drug development and so on,\u201d Niedernhofer says. \u201cWe need to go at this aggressively.\u201d<\/p>\n

 <\/p>\n

Aging as a modifiable process<\/strong><\/p>\n

Defined simply, aging is a time-dependent decline in function \u2014 of a cell, a tissue, a whole organism.<\/p>\n

For people, \u201caging starts when development ends, which means we start aging when we\u2019re in our 20s,\u201d says Laura Dugan, MD, who holds the Abram C. Shmerling, MD Chair in Alzheimer\u2019s and Geriatric Medicine at Vanderbilt, cares for elderly patients and directs a neuroscience research laboratory focused on the aging brain. \u201cAging certainly increases disease risk, particularly for diseases of the brain. Biologically, aging may be starting earlier than we think.\u201d<\/p>\n

A hint that aging may be a regulated process, rather than simply \u201cwear and tear\u201d over time, came from the recognition of differences in aging among animals.<\/p>\n

\u201cThere\u2019s an incredible range in life span in the animal kingdom, ranging from small insects that live for a few days to whale and shark species that live 200-plus years,\u201d says Kristopher Burkewitz, PhD, an aging researcher and assistant professor of Cell and Developmental Biology at Vanderbilt. \u201cThe aging process doesn\u2019t occur at a fixed rate; it varies widely. This was a major clue that biological aging, not chronological aging but biological aging, might be modifiable.\u201d<\/p>\n

It\u2019s also clear that the aging process varies widely between individuals of the same species. Centenarians who live to 100 and supercentenarians who live to 110 are being studied for insights into genetic, biological and lifestyle factors that increase longevity.<\/p>\n

The oldest documented person was Jeanne Calment of France, who lived to the age of 122, Dugan says. \u201cShe was riding her bicycle at 119, which tells us the potential is there to see improved aging in humans, if we can figure it out.\u201d<\/p>\n

Even for the tiny nematode worm, C. elegans, variation in the aging process is the norm. The average worm lives about three weeks in the laboratory.<\/p>\n

\u201cIn a genetically identical population where worms are all clones of each other, and they all live in exactly the same environment, a little petri dish, they vary in life span from two weeks to four weeks,\u201d says Burkewitz, who uses C. elegans as a model system to explore mechanisms of aging. \u201cUnderstanding the sources of this variability and how to predict it is one of the frontiers in the field.\u201d<\/p>\n

Studies in C. elegans laid the groundwork for the concept that genetic and biological signaling pathways control aging. In 1993, Cynthia Kenyon and colleagues at the University of California at San Francisco reported in the journal Nature that worms with mutations in a gene encoding an insulin receptor family member lived more than twice as long as wild-type worms.<\/p>\n

\u201cThis discovery that a single gene could have such a strong impact on the aging process was really shocking and opened up this hope that we could do something to intervene in aging,\u201d Burkewitz says.<\/p>\n

Deregulated nutrient-sensing (insulin receptor signaling is one aspect) is one of nine \u201challmarks of aging\u201d \u2014 processes that characterize aging at the cellular level and are active areas of research.<\/p>\n

\u201cThe hallmarks of aging are intertwined, and we don\u2019t know which are going to be best for targeting aging. It may be a combination,\u201d Niedernhofer notes.<\/p>\n

 <\/p>\n

The path to senolytics<\/strong><\/p>\n

Niedernhofer traces her interest in aging back to the first job she had in high school as a nurse\u2019s assistant in a nursing home, where she became passionate about helping elderly individuals maintain dignity.<\/p>\n

During college, she got curious about DNA damage and repair and worked for five years as a research assistant at Massachusetts Institute of Technology studying the impact of DNA damage on the structure of DNA.<\/p>\n

In the Medical Scientist Training Program at VUSM, Niedernhofer continued probing DNA damage \u2014 from endogenous molecules generated by lipid oxidation in cells \u2014 in the laboratory of Lawrence Marnett, PhD. After completing her doctoral degrees, she opted to forgo a residency to continue her research with a postdoctoral fellowship at Erasmus Medical Centre in Rotterdam, Netherlands, where she studied DNA damage in mouse models.<\/p>\n

\"\"
Laura Niedernhofer, MD\u201998, PhD\u201996<\/figcaption><\/figure>\n

It was there that her research interest in DNA damage and repair and her earlier passion for the elderly came together.<\/p>\n

\u201cI wanted to understand the health impact of DNA damage if you don\u2019t repair it, and that just beautifully segued into aging. DNA damage is a hallmark of aging. What does the damage do? It causes cellular senescence (cells stop dividing but don\u2019t die), and that drives aging,\u201d Niedernhofer says. \u201cIt all kind of fell together.\u201d<\/p>\n

Niedernhofer and her colleagues developed mouse models with genetic defects in DNA repair mechanisms and showed that removing DNA repair mechanisms causes accelerated aging.<\/p>\n

\u201cIt was absolutely crystal clear that mice that can\u2019t repair DNA damage age fast,\u201d she says.<\/p>\n

Mutations that impact DNA repair have also been identified in people with progeroid syndromes \u2014 rare genetic disorders that cause clinical features of aging, such as hair loss, skin tightness, osteoporosis and cardiovascular diseases, at a young age. Mouse models of these syndromes are an important tool for aging research.<\/p>\n

DNA damage that isn\u2019t repaired \u2014 or other cellular stressors \u2014 triggers a signaling cascade that stops DNA replication and cell division and sets up a state of permanent arrest called senescence.<\/p>\n

\u201cThe purpose of senescence is to prevent cancer; it\u2019s a brilliant, evolutionarily conserved strategy,\u201d Niedernhofer says.<\/p>\n

But senescent cells, which \u201clook like fried eggs,\u201d change gene expression patterns and secrete pro-inflammatory and other destructive molecules. They need to be removed and are, in a process that happens readily in younger individuals, but slows with aging.<\/p>\n

Scientists at the Mayo Clinic developed a mouse model with a drug-inducible \u201csuicide\u201d gene, that when activated, killed senescent cells. Their 2011 paper in Nature demonstrated that clearing senescent cells delayed the onset of age-related pathologies in a progeroid mouse model.<\/p>\n

\u201cThese studies gave us confidence that senescent cells truly drive aging,\u201d Niedernhofer says. \u201cIf we could clear them and improve health span with genetic tricks, then we could certainly do this with drugs.\u201d<\/p>\n

Niedernhofer and her colleagues screened drug libraries in DNA repair-deficient cells that senesce in culture; their Mayo Clinic colleagues used a bioinformatics approach. In 2015, they reported on a new class of drugs: senolytics, which selectively kill senescent cells. A combination of the cancer drug dasatinib and the natural plant product quercetin killed senescent cells and extended health span in progeroid mice. A single dose improved cardiovascular measures and exercise capacity in normal, aged mice.<\/p>\n

 <\/p>\n

Anti-aging drugs within the decade?<\/strong><\/p>\n

There are about 30 clinical trials currently testing senolytics, Niedernhofer says. A challenge, she notes, is that many of the drugs are natural products; her favorite is fisetin, which is abundant in strawberries.<\/p>\n

The current trials of senolytics aim to show that the drugs reduce senescent cells, are safe, and perhaps offer some improvement in diseases like idiopathic pulmonary fibrosis, chronic kidney disease, osteoarthritis and even COVID infection. In the meantime, Niedernhofer and her colleagues are working to develop new senolytics that will interest pharmaceutical companies and fuel more research.<\/p>\n

And senolytics are not alone. Multiple efforts are targeting other hallmarks of aging with resveratrol and related compounds, metabolites like NAD, and rapamycin.<\/p>\n

But the current trials do not directly address the big questions of geroscience: Can drugs target aging itself? Can one drug delay disease onset or treat more than one disease at once?<\/p>\n

Currently, the Food and Drug Administration does not consider old age, or frailty, a druggable target. The Targeting Aging with Metformin (TAME) trial will test whether individuals taking metformin, a commonly used diabetes drug, have delayed development or progression of age-related chronic diseases such as heart disease, cancer and neurodegenerative disease. Metformin appears to influence multiple hallmarks of aging and has been shown to delay aging in animal models. Once it is fully funded, the TAME trial plans to enroll 3,000 individuals ages 65-79 at 14 sites across the country.<\/p>\n

\u201cI think we will have an answer within this decade about whether this is really going to work,\u201d Niedernhofer says. \u201cAnd then it\u2019s going to take a lot of fine-tuning.<\/p>\n

\u201cWe\u2019re also going to need biomarkers to determine which type of aging therapeutic someone needs. I think this will become a personalized medicine approach because we\u2019re all different; we all age differently.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"

When someone asks her age, Abrie Pillow says that she\u2019s 10. \u201cI\u2019m 82, but I put the eight and two together as a joke,\u201d she laughs. Pillow is energetic and busy, with gardening and other projects at home, church and community volunteer work, family gatherings and great grandchildren sleepovers. She and her husband, Joe Nickerson,…<\/p>\n","protected":false},"author":219,"featured_media":3477,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2},"_links_to":"","_links_to_target":""},"categories":[14,44],"tags":[],"class_list":["post-3404","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-vm-features","category-vm-spring-2022"],"acf":[],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/cdn.vanderbilt.edu\/t2-main\/medschool-prd\/wp-content\/uploads\/sites\/82\/2022\/05\/feature5.jpg","jetpack_sharing_enabled":true,"jetpack_shortlink":"https:\/\/wp.me\/pcDnub-SU","_links":{"self":[{"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/posts\/3404","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/users\/219"}],"replies":[{"embeddable":true,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/comments?post=3404"}],"version-history":[{"count":2,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/posts\/3404\/revisions"}],"predecessor-version":[{"id":3478,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/posts\/3404\/revisions\/3478"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/media\/3477"}],"wp:attachment":[{"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/media?parent=3404"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/categories?post=3404"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medschool.vanderbilt.edu\/vanderbilt-medicine\/wp-json\/wp\/v2\/tags?post=3404"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}