Longevity Genes, Blood Biomarkers of Aging, & Targeting Aging with Metformin with Dr. Nir Barzilai

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Aging is inevitable, but can we influence how we age? In this episode of Longevity by Design, hosts Dr. Gil Blander and Ashley Reaver, MS, RD, CSSD,  interview Dr. Nir Barzilai—the Director of the Institute for Aging Research at the Albert Einstein College of Medicine and the Director of the Paul F. Glenn Center for the Biology of Human Aging Research and of the National Institutes of Health’s (NIH) Nathan Shock Centers of Excellence in the Basic Biology of Aging—during which he discusses groundbreaking research on aging. 

This is an enlightening discussion with Dr. Barzilai on factors influencing healthspan and lifespan, and the paradigm-shifting idea of targeting aging to extend healthspan and lifespan. He shares fascinating insights from his research on the influence of genetics and lifestyle on healthspan and lifespan, and blood biomarkers of aging. The conversation sheds light on the emerging scientific evidence and paradigm-shifting concept for medical interventions (gerotherapeutics) to extend healthspan and lifespan by targeting the underlying biology of aging.

The episode wraps up with actionable insights for listeners interested in enhancing their healthspan and longevity. Dr. Barzilai discusses the importance of personalized health strategies, integrating cutting-edge research with everyday health practices while emphasizing the importance of a holistic approach. As a listener, you will leave equipped with knowledge and science-backed ways to navigate your personal health journey and help you live healthier longer.

Episode highlights

• Introduction: 00:00-04:13
• Why Dr. Barzilai’s studies centenarians and their children: 04:14-10:07 
• Do centenarians live longer with poor health or live healthier longer? 10:08-13:07
• Does becoming a centenarian have a strong genetic influence?: 13:08-15:41
• How do growth hormone and IGF-1 affect healthspan and lifespan?: 15:42-23:39
• What other genes affect healthspan and lifespan?: 23:40- 26:51
• Does low IGF-1 negatively impact muscle and physical function?: 26:52-28:40
• What are the effects of ethnicity and socioeconomic status on longevity?: 28:41-30:57
• What is the effect of lifestyle, nutrition, and exercise on the longevity of centenarians?: 30:58-34:07
• Do women or men live longer?: 34:08-37:55
• Why do women live longer than men?: 37:56-41:38
• Biomarkers of aging and biomarkers of organ aging: 41:39-47:07
• What is metformin, and what is the purpose of the TAME trial?: 47:08-51:37
• Do you think metformin will improve healthspan and lifespan?: 51:38-54:20
• Does metformin only improve blood glucose control, or does it benefit health and aging in other ways? 54:21-56:50
• Is metformin good for older adults but not young adults?: 56:51-57:45
• How does the combination of metformin and exercise impact muscle size (hypertrophy) and strength?: 57:46-01:00:45
• Should everyone take metformin?: 01:00:46-01:03:13
• Dr. Gil Blander’s and Dr. Nir Barzilai’s personal humorous anecdotes on exercise: 01:03:14-01:04:32
• Is there a reason and explanation for why metformin did not show an effect on lifespan in mice in the Interventions Testing Program (ITP)?: 01:04:33-01:07:01
• Are GLP-1 agonists beneficial for healthspan and lifespan?: 01:07:02-01:10:55
• Are there tradeoffs with using GLP-1 agonists?: 01:10:56-01:11:43
• What are the top 5 gerotherapeutic candidates for improving healthspan and lifespan?: 01:11:44-01:15:10
• Dr. Nir Barzilai’s top tip for improving health: 01:15:11-01:19:29

About Dr. Nir Barzilai

Dr. Nir Barzilai is the director of the Institute for Aging Research at the Albert Einstein College of Medicine and the Director of the Paul F. Glenn Center for the Biology of Human Aging Research and of the National Institutes of Health’s (NIH) Nathan Shock Centers of Excellence in the Basic Biology of Aging. He is the Ingeborg and Ira Leon Rennert Chair of Aging Research, professor in the Departments of Medicine and Genetics, and member of the Diabetes Research Center and of the Divisions of Endocrinology & Diabetes and Geriatrics.

Dr. Barzilai’s research interests are in the biology and genetics of aging. He studies the genetics of longevity, and his studies on families of centenarians have provided genetic and biological insights on genes and factors that delay aging and protect against age-related diseases. Several drugs are developed based, in part, on these paradigm-changing studies. Dr. Barzilai is also leading the TAME (Targeting Aging with Metformin) to prove the concept that multi-morbidities of aging can be delayed by metformin, working with the FDA to approve this approach which will serve as a template for future efforts to delay aging and its diseases in humans (https://www.afar.org/tame-trial). 

He has authored over 300 peer-reviewed papers and was a recipient of numerous prestigious awards, including the 2010 Irving S. Wright Award for Distinction in Aging Research and the 2018 recipient of the IPSEN Longevity award.  He is on the board of AFAR, and its scientific director and a founding member of the Academy for Healthspan and Lifespan, The Longevity Biotech Association, and the Healthy Longevity Medicine Society. He also co-founded two biotech companies–CohBar and Lifebiosciences. Dr. Barzilai has featured in prominent papers, podcasts, TV programs, documentaries, TED talks, consulting for the Singapore government several International Banks, The Vatican, Milken Institute, and Davos Economic Forum. His book Age Later was published in June 2020.

Unraveling the genetic blueprint of centenarians

Dr. Nir Barzilai's research sheds light on the genetics of centenarians, those who live to or beyond 100 years, revealing that they possess unique genetics (longevity genes) that contribute to their extended lifespan and healthspan, despite having genotypes associated with diseases like Alzheimer's, cardiovascular diseases, and diabetes.

“It's not that they (centenarians) have the perfect genome, but they have genotypes that are slowing their aging,” says Dr. Barzilai.

Not only do centenarians experience delayed onset of age-related diseases, but they also exhibit a contraction of morbidity, meaning they suffer from age-related diseases or disability for a significantly shorter period of time towards the end of their lives. 

"We showed that our centenarians, compared to people who live now…get diseases 20, 30 years later. So it's not only the lifespan, it's the healthspan. And that's not even the most interesting thing we found. Those people have what's called a contraction of morbidity. They're sick very little time at the end of their lives…when they look by age, you can see that the medical cost in the last two years of centenarians is a third of those who die at 70…they live healthier and have contraction of morbidity. And that has a huge consequence from the point of view of longevity dividend and what it means for the economy if we can make people healthier and not sicker,” says Dr. Barzilai.

These insights indicate that genes strongly influence our body’s aging process, highlighting that the aging process itself, when slowed, can mitigate the onset of age-related diseases.

The IGF-1 pathway's role in aging and longevity

The growth hormone Insulin-like Growth Factor 1 (IGF-1) pathway is important in early life for growth and development and plays a pivotal role in lifespan and healthspan. Dr. Barzilai’s research has shown that IGF-1 interacts with age to modify risk in a manner consistent with the antagonistic pleiotropy hypothesis of aging—something that is beneficial for us in young age but is detrimental in older age. High IGF-1 in older adults has been observed to be detrimental as it is linked with an increased risk for developing chronic diseases such as dementia, Alzheimer’s, cardiovascular diseases, diabetes, and osteoporosis, and death, whereas high IGF-1 in young adults is linked to a lower risk of disease and death.

A commonly proposed concern of low IGF-1 in older age is that it may be detrimental for muscle health and physical function. However, Dr. Barzilai's work shows that lower levels of IGF-1 in centenarians are associated with longer lifespans and better cognitive function without the trade-offs of decreased muscle strength or physical function. 

These discoveries highlight the complex nature of the IGF-1 pathway in aging, where what benefits us in youth can become detrimental in old age, embodying the concept of antagonistic pleiotropy.

Differences in aging and longevity between men and women

Approximately 80% of individuals who live to become a centenarian are women. Dr. Barzilai’s research investigating blood biomarkers of aging found that in older adults aged 65-95 years, showed that women have more stable blood biomarkers as they age than men.  Of the age-associated changes in blood biomarkers, women had more than 50% fewer changes than men. These findings may indicate that compared to men, women age slower and why more women live to become centenarians.

Metformin's potential in extending healthspan and the TAME trial

Metformin, a drug commonly used to treat type 2 diabetes, has also been shown to extend healthspan and lifespan. Dr. Barzilai discusses the ongoing research into metformin's effects beyond glucose control, including its ability to reduce the risk of developing age-related diseases such as diabetes, cardiovascular diseases, some cancers, cognitive decline, and death.

The mounting scientific on the ability of metformin to extend healthspan and lifespan, and it’s safety profile, led Dr. Barzilai to spearhead the development of the TAME (targeting aging with metformin) trial. The goal of the TAME trial is to test the idea that age-related diseases and death can be delayed by metformin, working with the FDA to approve this approach.

Rather than the current medical model of treating aging one disease at a time, the TAME trial represents a paradigm shift in healthcare and will serve as a template for future efforts to investigate medical therapies to delay aging and age-related diseases in humans.

Gerotherapeutic candidates for extending healthspan and lifespan

Many common chronic diseases and syndromes are aging-related, says Dr. Barzilai. This raises the prospect that therapeutic agents that target the biological changes of aging will prevent or delay multiple diseases with a single therapy. Gerotherapeutic drugs are those that target pathways involved in aging, with the aims of reducing the burden of aging-related diseases and increasing lifespan and healthspan. Based on the discussion with Dr. Barzilai and his research, the most promising gerotherapeutic drugs include:

• SGLT-2 inhibitors
• GLP-1 agonists
• Metformin
• Zoledronate
• Acarbose
• Rapamycin/rapalogs
• Methylene blue
• ACE inhibitors/angiotensin receptor blockers
• Dasatinib and quercetin

Top tip for healthspan

Other than being born to the right parents and inheriting the genetic makeup of centenarians, Dr. Barzilai emphasizes the importance of a holistic approach to health, including exercise, a healthy diet, social connections, and seeing your doctor regularly. He also recommends testing your blood biomarkers regularly because having this data helps inform more personalized ways of improving health.

"Longevity medicine is going to be about us taking our Fitbits and stuff, getting our data, and having an app that will tell us how to maximize our health, when to take medicine, and what medicine we should take," says Dr. Barzilai.

Similar Longevity By Design episodes we think you would love: 

• Dr. Nir Barzilai—Genetics and Lifestyle Factors of Centenarians 
• How to Improve Your Healthspan Using DNA Insights with Dr. Bartek Nogal
• Dr. Ali Torkamani—Genomics and Aging

Longevity by Design