In this new interview, David Sinclair, Harvard professor and the author of Lifespan, explains his theory of aging, shares parts of his health routine, and reveals which directions in todays aging research excite him.
In the longevity field, when it comes to name recognition, theres David Sinclair and all the rest. Like in many other areas, this gap in popularity doesnt necessarily reflect the actual professional hierarchy. Dr. Sinclair, a Harvard professor, is undoubtedly a very prominent aging researcher, but he would probably agree (although we didnt ask) that he has many equally worthy colleagues.
Some of Dr. Sinclairs popularity stems from his highly successful Lifespan: Why We Age and Why We Dont Have To, a great entry-level book that did a lot to introduce the science of aging and the ideology of life extension to the public consciousness. Now, a new book is in the works, and it differs from the first one, Dr. Sinclair told us, in that Lifespan is the textbook, Lifespan II is the guidebook. That probably means we can expect some expert wisdom on how every one of us can stay healthier and live longer. Dr. Sinclair maintains an interesting personal routine, which we also asked him about.
Today, Dr. Sinclair is one of the most visible longevity advocates, expertly broadcasting the message of life extension from top-tier platforms such as Joe Rogans and Peter Diamandis podcasts. He carefully chooses his appearances at conferences, where he receives rock star-like attention.
All this does not mean that Dr. Sinclair has completely morphed into a public figure. On the contrary, he and his team at Harvard continue to produce some of the most interesting results in the field, which we have covered extensively. He is one of the pioneers in practical applications for partial cellular reprogramming, having demonstrated that it can regenerate crushed optic nerves in mice and non-human primates.
Like many high-profile researchers, Dr. Sinclair has his pet theory of aging. The current ruling paradigm is the Hallmarks of Aging, the processes that include genomic instability and telomere attrition. Together, they are responsible for the phenotype of aging that we are all familiar with. Scientists know that many if not all these processes are interconnected, but is there an actual hierarchy?
Dr. Sinclairs answer to that is yes. According to his Information Theory of Aging, cells health and function depend heavily on epigenetic information, a set of instructions in the form of slight chemical alterations to DNA molecules that governs the expression of genes and other elements of our DNA, such as retrotransposons. This is what tells cells into which cell type they should differentiate and how they should perform this types duties.
With time, various stressors throw our epigenome into disarray. Imagine pages of a manual being accidentally torn out, having coffee spilt over them, and so on. Epigenetic alterations are indeed one of the Hallmarks of Aging, and their contribution to aging is widely acknowledged. However, Dr. Sinclair takes it one step further.
First, those changes, he says, are responsible for a very significant part of aging that is, they are high upstream and influence many or all other hallmarks. Second, he postulates that there is a copy of the manual that can be used to restore the epigenome to its youthful state. We can see hints to this in cellular reprogramming, where cells can be either thrown back to their pluripotent (undifferentiated) state and almost completely rejuvenated, or partially reprogrammed and partially rejuvenated.
If we can find that pristine backup copy of cellular epigenetic information and learn how to use it, the possibilities are endless. A recent study by Sinclair et al. presents findings in support of the theory. Its not conclusive evidence yet, but definitely hope-inspiring. For more on this and other topics, we turned to David himself, and he kindly agreed to answer a few questions.
According to the Information Theory of Aging, epigenetic changes that disrupt gene expression patterns as we age are driven by cell stress and damage, such as DNA breaks. This process causes cells to lose their function and identity, to become exdifferentiated, and this may be a cause of many of the changes seen during aging, including some major age-related diseases.
Its not yet known how potent the effects of in vivo epigenetic reprogramming will be. We know it can improve the function of the eye to cure blindness in mice and monkeys and even improve the function of the brain, but whether it can fix the many problems that occur with age in the human body is not known.
The hypothesis predicts that there is chemical information in cells that encodes the youthful structure of the epigenome so that it can be reset, and gene expression can be restored to an earlier age. We know that it is possible to reset gene expression. We dont yet know for sure how and where this information is stored, but we are working hard to find these answers.
The hypothesis is that the backup copy stores the cells youthful chromatin structure that controls which RNAs and proteins are expressed. Resetting these structures allows the cell to regain its differentiated state and its youthful functions.
The hypothesis is that rejuvenation is important for germ cells and embryos to maintain youth. We speculate the putative backup copy is also important for the rebuilding of damaged organs and tissues. Many species can regrow entire body parts, from limbs to heads. With the exception of our livers, which can regrow after damage or surgery, we humans have largely lost the ability to regrow organs and limbs.
Species that live a long time are known to have a more stable epigenome than those that live shorter. We suspect this might be because they are better at preventing and repairing DNA damage, which we have shown can accelerate age-related changes.
Antagonistic pleiotropy is a process that is advantageous when organisms are young, but they cause problems later in life, when the force of natural selection is so weak they continue to exist in the germline. The processes that disrupt the epigenome seem to be useful in young organisms because they recruit chromatin factors to sites of broken DNA and increase DNA repair and stabilize chromosomes. We first saw this in yeast cells in Lenny Guarentes lab in the late 1990s, then later in mammals, in my own lab in the 2000s. The problem is that the recruitment doesnt reset fully, and chromatin regulators lose their place on the genome, causing exdifferentiation of cells. In 2007, we called this the Relocalization of Chromatin Hypothesis of Aging or RCM, and it was later incorporated into the Information Theory of Aging.
We have not seen any evidence for this claim after a decade of studying the system, the results of which are in the paper showing cells do not experience cytotoxicity. Our detailed response to the claim has been published in Cell.
We have a long way to go. Most people havent heard of aging research or the results that are being produced. Most doctors are also unaware of the advances in the field.
I think our biggest bottleneck is having access to old mice that we can study. One solution would be to have a source of them for all researchers.
Saying there is no known upper limit doesnt mean we can live for decades or centuries longer. I dont know of any technology that would allow Longevity Escape Velocity currently, but I also know saying something is impossible is a dangerous thing in this time of human history.
Im excited about senolytics, epigenetic reprogramming, and the use of AI in healthcare.
I have hopes we will be able to rejuvenate people in the next few decades. If all goes well, Life Biosciences will be testing vision restoration in humans in 2025.
Im not simply relying on anecdotes. Changing my lifestyle has resulted in changes to my blood biomarkers that are consistent to long-term health. Vegan diets are considered some of the healthiest of all, and this is backed by multiple human studies. Skipping meals so that my eating window is shorter, which is what I try to do, is backed by evidence indicating that it improves metabolic health and lowers inflammatory markers, among other benefits.
We know their safety profile. Metformin has been in tens of millions of people. Metformin and low-dose rapamycin appear to be relatively safe. Whether they are effective at slowing aging and safe in combination is not yet known.
After this interview was taken, David Sinclair has stepped down as President of the Academy for Health & Lifespan Research, as announced on X by another co-founder, Nir Barzilai.
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David Sinclair on Solutions Within Decades - Lifespan.io News
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