Life Extension Magazine®

Genes unraveling as described in the Juvenescence

Jim Mellon and Al Chalabi

The authors of Juvenescence: Investing in the Age of Longevity, explain the recent progress of scientists and companies in understanding the key molecular causes of aging.

Scientifically reviewed by Dr. Gary Gonzalez, MD, in August 2023. Written by: Garry Messick.

Jim Mellon and Al Chalabi are successful investors and entrepreneurs whose interest in longevity research and its related technologies led them to write their new book, Juvenescence: Investing in the Age of Longevity.

The two are so excited about the potential in this area that, along with several other partners, they have started a company called Juvenescence, named after their book, with the mission of finding diagnostic and therapeutic agents to treat aging and diseases associated with aging.

In Juvenescence, the authors put forth the proposition that the research community is on a fast track to properly understanding the metabolic pathways involved in cellular aging. Dr. Greg Bailey, a cofounder of the company, writes in the forward that the book will “tell you about the scientists and companies who are working on these products as well as outlining the key pathways.”

The book shines a light on recent scientific progress in understanding the key molecular causes of aging, and explains why this understanding is essential to the development of effective therapeutics.

In their interview with Life Extension®, Mellon and Chalabi outline some of the general ideas that make longevity research such a promising field, and touch on a few specific areas of interest.

LE: Let’s start with the basic idea of aging. What exactly is it?

JM & AC: Aging is rigorously described as senescence, the progressive degradation of bodily functions. Sir Peter Medawar, a British pioneer in aging research in the 1940s, described aging as an “unsolved problem of biology.” Medawar proposed that some genetic mutations only have deleterious effects late in life and are not “selected out” by evolution, as evolution is concerned primarily with reproductive fitness and not necessarily with the prolongation of life. He suggested that increasing age features a decline in the strength of natural selection.

LE: You mentioned senescence. Could you describe that process in cellular terms?

JM & AC: Molecules become unbound, genes become inefficient, waste products (cellular debris) build up and we (and other organisms) die. Organisms of all types accumulate damage to cells, tissues, organs, and indeed to all basic molecules, causing genomic instability to set in. Along with this comes shortening of the telomeres, reduced mitochondrial function (limiting energy production), the depletion of the potency of stem cells, and impaired intracellular networks.

LE: How do you feel about the prospects for longevity?

JM & AC: We really can—and probably will—live much longer than most people think is feasible. Science is advancing so rapidly that it is hard to comprehend the full implications of many of these recent discoveries, so we have tried to distill the ones we’re familiar with into our book.

We have spent a year researching, interviewing, collating, filtering, pleading, harassing, and reading, as well as driving 7,000 miles around the US. Finally, we have arrived at our one central conclusion: The current pause in rising lifespans in some developed countries, including in the UK and the US, is only temporary. Babies born today are likely to live well over 100, and probably a lot longer than that. Techniques which are available to us beyond those of the fairly obvious admonitions concerning diet, sleep, exercise, and the avoidance of sugar and tobacco could carry most adults alive today to well over 100. Those techniques are building a bridge to a new world.

LE: What do you foresee as being on the horizon?

JM & AC: This new world is one where drugs, genetic engineering, cellular enhancements, and organ replacements, amongst other interventions, will add decades to our potential lifespan, taking most people much closer to the maximal life length that only a few supercentenarians currently enjoy.

The bridge that is being built is one made partly of drugs and therapies that address the main diseases of aging, namely cardiovascular disease, cancer, neurodegeneration, diabetes and respiratory disease.

In addition, the development of therapies to remove senescent cells, to restore cellular activity, to improve hormonal balance and to enhance mobility in older people is proceeding apace. If people can hold on to healthy life for the next decade or so, the chances are that they will eventually start to gain more than one year of life expectancy for each year that they live. The old nostrums about three score and ten, about being “illderly” in old age and of the inevitability of a preordained early expiration while in a diseased state are quickly being debunked.

LE: You seem to think the field of anti-aging medicine is about to really take off. Why?

JM & AC: First, the research tools available to scientists are improving rapidly, particularly in the field of genomic sequencing, in the management of big data, and in the use of non-animal models to get scientific answers much faster than by conventional means.

Second, because so much information has now been discovered about the pathways, genes, and proteins that are implicated in aging and so much chemistry has been done on what might interfere with them, the trials of therapies designed to influence lifespan are imminent. Some compounds which might influence lifespan are available right now, even if anti-aging properties can’t yet be definitively claimed for them.

One of the problems of aging research is that people live a long time and trials involving humans have to be designed over long periods, making them expensive and time-consuming. That’s why alternative models of aging are so useful and computer simulations are becoming increasingly vital to getting to the important points of discovery.

Scientists in the field of biomedical gerontology (longevity and anti-aging) have been working hard to identify the many genes and pathways that are implicated in aging and in determining which ones are more important than others. A great deal of progress has been made here, and such things as mTOR, IGF-1/insulin signaling, Sestrins, FOXO3A, sirtuins, ApoE, CETP, daf-2, and AMPK, to name a few, are now revealed as being important to the aging process.

LE: Could you expand a little on AMPK and its activation via metformin?

JM & AC: Metformin is an antidiabetic drug that increases insulin sensitivity as well as activating the enzyme AMPK (adenosine monophosphate activated kinase), thereby positively modulating glucose levels and levels of circulating lipids in the body. It also seems to regulate a variety of processes relating to aging.

AMPK seems to play a critical role in the regulation of our energy balance, particularly in restoring mitochondrial function. Exercise and caloric restriction have an effect in activating AMPK, as does metformin. AMPK also appears to inhibit the mTOR pathway, which is an important clue to metformin’s role in anti-aging. And mTOR has been linked to several age-related diseases such as cancer, cardiovascular disease, and Alzheimer’s.

LE: You mentioned alternative models of aging. Can you give an example?

JM & AC: There is now a vast array of research into two of the most popular proxies of aging, worms and yeast. Data from both species indicate that a commonality, or conservation, of the mechanisms that cause late-life decline exists in both of them. This is even though their evolutionary paths diverged at least a billion years ago.

Humans also appear to have these conserved pathways linked to aging. “Conserved” simply means that some of the DNA sequences appear to have remained relatively unchanged far back in time, as revealed by the “tree of life,” the so-called phylogenetic tree. This is in spite of speciation, which is the division of organisms into different species over a long evolutionary period.

It is the prospect of manipulating our fundamental biology and of overcoming the conservation of pro-aging genetics that makes longevity such an exciting area. For the first time in history, a concerted and significant effort is being made to unravel the roles that the multitude of bewildering pathways, genes, and other factors, play in aging.

LE: One area of research that you find promising is parabiosis, the practice of joining a young organism to an older one.

JM & AC: Tom Rando of Stanford University announced in 2005 that heterochronic (different stages of development) parabiosis, where two mice of different ages were conjoined by surgery, restored the livers and muscles of the older one. The positive effect of blood transfusions from young to old may be because older people have a lesser supply of blood stem cells in their bone marrow than the supply that younger people enjoy. These blood stem cells are progenitors for our red and white blood cells, and so a diminished quantity of them leads to anemia and a weakening of the immune system.

Additional benefits to the older subject include improved cardiac muscle tissue, enhanced cognition and what is known as remyelination (bolstering the sheaths of axons in the central nervous system)…there is no doubt that regeneration occurs in the older animal during this process, which is encouraging for longevity research.

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LE: Your view of the potential for increased human longevity is quite optimistic, isn’t it?

JM & AC: Just a few years ago, the possibility of ultra-long life (over 110) becoming commonplace was envisioned only by people thought to be “crackpots” or “charlatans.” But today, one by one, the challenges to such ultra-long lifespans are being overcome. The ramparts protecting aging as a defined and immutable condition are being stormed.

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