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What Have We Learned About Aging? - Charles Brenner, PhD

Torah recounts extraordinary lifespans including some numbering in the hundreds of years. Our matriarch, Sarah, was also said to become a mother at the age of 90. Given that Rosh Hashona is celebrated as the birthday of the world and our Hebrew year says we are in 5782, few among us would look to scripture as a source of accurate information about geological or biological time. However, it is always interesting to consider our written heritage when we consider questions about life on earth.

In contrast to the account in Genesis 1, living things evolved on this planet over 3 to 4 billion years. Life was unicellular for the first 2 billion of those years, during which time genes evolved that encode fundamental metabolic processes like DNA replication, fuel oxidation and making complex molecules from simple ones.

There have been animals for approximately 600 million years. The animal body plan with food entering at one end and waste coming out on the other is common to animals and so are genes that specify these basic features. Single genes have been identified that can make an animal more heat resistant, longer or fatter, among other things.

Mammals have been evolving for ~225 million years and primates for ~85 million years. Estimates for human origins date to merely 300,000 years ago, which is fewer than 20,000 generations back.

Things are the way they are in biology because gene sets—instructions written in our DNA—encode physical properties that have been subject to mutation and selection. Gene sets limit what is possible for an organism to do. Organisms that are adapted to life at high temperatures can be selected for resistance to even higher temperatures. However, properties that don’t confer a survival advantage are not propagated to next generations.

We’ve learned that animal gene sets confer the ability to recognize and seek out food, avoid predation, survive famine, seek mates, and reproduce and take care of young until the offspring can do these things for themselves. Thus, animals generally are capable of reproducing relatively early in their lives and can undergo multiple cycles of reproduction during their lifetimes. “Multiplying like rabbits” thus entails early fertility, high fecundity, high survival, and the ability of mother and father rabbits to produce multiple broods.

Characteristic lifespans are encoded in the gene set of every species. While mice live for about 2 years, there are mole rats that can live for 10 times that long. But this does not mean that there are single or small numbers of genes that give mole rats ten times the lifespan of mice. Rather, it appears that the entire gene set works together to produce male and female mole rats with strong enough hearts, brains, respiratory and muscle systems to provide for themselves for two decades, and to have sufficient sexual and reproductive and caretaking abilities to be parents as elderly 20-year old rats.

While animal fertility declines in old age, animals generally retain reproductive capacity from their initial sexual maturity for the remainders of their lifespan.  Seen in this manner, longevity is considered an emergent, multigenic property of animals that supports the function of all their vital systems for as long as they live. Longevity is therefore unlike simple traits like heat resistance that can be under direct selection.

Humans represent the exception that proves the rule that connects fertility with lifespan. While men retain a declining level of fertility throughout our lives, women reach menopause typically at least a generation prior to their expected lifespan. This is understood to be a function of the inability of human children to take care of themselves. Because women have such an important role in child-rearing, women evolved the unusual capacity to outlive their reproductive capacity, thereby ensuring that their children and grandchildren survive to pass on their genes.

And while old men produce some motile sperm in our dotage, the mutational burden of old sperm is very high. The fact that 80-year old guys can’t compete with 20-year old guys in sex appeal tends to keep harmful mutations out of the gene pool and actually selects against—not for—genes that would be associated with longevity.

In recent years, claims have been made that scientists now understand how we age and that we do not have to age. According to this view, longevity genes identified in more primitive life forms and also found in people can be activated so that people do not have to age. Unfortunately, the claims are untrue: the genes identified in yeast do not extend lifespan in animals and there have not been identified miraculous elixirs that extend the lifespan of healthy humans. Obviously there are medicines for a wide variety of illnesses that can add years to life and life to years but there is no pharmaceutical longevity hack for the worried well.

Analysis of data on lifespan supports what appears to be a ~120 year limit on human lifespan. Average life expectancy has increased dramatically in the last two centuries largely due to cleaner water, better availability of high quality nutrition, antibiotics, vaccines and other public health measures. Countervailing trends in recent years have limited achieved lifespan due to obesity-associated diseases, gun violence, drug use and other mental health problems, and the coronavirus pandemic. Thus, while it is relatively straightforward to underachieve our lifespan potential with poor metabolic health, infectious diseases, accidents or violence, it is not clear that we have the ability to extend genetically encoded maximal lifespans.

From a Jewish point of view, three points are worthy of consideration.

  1. Individual human lives are precious, precisely because they are limited. To save a life, pikuach nefesh, is to save the world.
  2. Tales of patriarchs and matriarchs living beyond 120 are legendary and not to be taken as literal truth. Similarly, for Sarah to have become a mother at 90—a superhuman feat—is clearly an account of “signs and wonders” that one cannot expect to see.
  3. In Deuteronomy 13, Moses warned us about false prophets who may even have “signs and portents” that appear to be true. Rabbi ibn Ezra further explained that we are being tested and that signs have to pass the test of reason. I feel obligated to warn laypeople that despite best-selling books and major investments in longevity research, the flashiest signs and portents about not having to age are not evidence-based.

It is clearly possible to accelerate aging and not reach our biological potential. Additionally, with good old-fashioned improvements in physical activity and diet, we can improve our aging. Nonetheless, all of us age. Let us use our culture’s respect for maturity to embrace our aging and not deny our mortality.

As we head into spring, I wish you all the joy of watching bulbs rise from the earth, and the joy of growing your own karpas for pesach.

by Charles Brenner, PhD


Dr. Brenner is the Alfred E. Mann Chair of City of Hope’s Department of Diabetes & Cancer Metabolism and the chief scientific advisor of ChromaDex, Inc. His research concerns nicotinamide adenine dinucleotide (NAD), the central catalyst of metabolism, and has led to the development of Tru Niagen, a nutritional supplement he endorses to help people age better. Brenner jousts with dreamy-eyed immortalists on twitter (@charlesmbrenner), where he’ll take your questions on metabolism, nutrition and healthy living.

Tue, June 28 2022 29 Sivan 5782