Lifespan: Why We Age―and Why We Don’t Have To

“He was going to live forever, or die in the attempt.” – Joseph Heller, Catch 22

What if we treated aging as a disease? Already you can imagine the controversy. It would feel wrong to call granny sick just because she’s old. Aging has always been integral to the human experience. Generations of forefathers lived predictable lifespans with predictable maximums.

David Sinclair, a researcher at Professor at Harvard Medical School, believes that’s about to change. He argues in Lifespan: Why We Age―and Why We Don’t Have To that there’s no law of nature that says humans have to die at a certain age, but there is an underlying cause. If we discover the cause of aging, maybe we can slow or reverse it. Sinclair’s Information Theory of Aging might be that discovery.

Sinclair’s Information Theory of Aging posits that aging is the result of information loss at our bodies’ epigenetic level. Epigenetics regulate how and when our genes express. If our genes are like computer code, epigenetics are the keyboard that enters commands. As our epigenetic information is lost, we see the hallmarks of aging: genetic instability, shortened telomeres, mitochondrial dysfunction, cellular senescence, and more.

This is such a big idea that I spent weeks seeking informed opinions opposed to Sinclair. Frankly, none hit the mark. The biggest criticism of anti-aging science is a lack of experimental human research. There are many animal studies but relatively few controlled human experiments. Any one of them alone proves nothing, but together they are very compelling. I believe Sinclair’s logic and data are strong, and I’m excited for additional research results.

The mechanics of aging

Long ago, a single-cell organism evolved a genetic circuit essential to survival. When external forces damaged its DNA, its genes diverted resources away from cell division (reproduction) and toward DNA repair. This trade-off promotes cell survival by not spending resources reproducing damaged DNA.

This trade-off is also, per Sinclair, the cause of aging. Mammal cells carry an advanced repair/reproduce circuit, with seven genes that create sirtuins (SIRT1 to SIRT7). Sirtuins are proteins that regulate core cellular functions. They require a molecule called nicotinamide adenine dinucleotide, or NAD. Sinclair believes that age-related NAD loss and the resulting decline in sirtuin activity is the main reason older bodies develop more disease.

Scientists have discovered other longevity-related genes that create proteins like mTOR (mammalian target of rapamycin) and enzymes like AMPK (AMP-activated protein kinase). Modulating these longevity genes triggers a daisy chain that causes cells to hunker down and repair damage, rather than spend energy dividing.

The effects of aging

Aging, therefore, is the underlying cause of the diseases we see in elderly populations: cancer, Alzheimer’s, COPD, Osteoarthritis, Sarcopenia, etc.

Modern healthcare is like “whack-a-mole.” We treat whatever disease emerges and then wait for the next to pop up. Playing this game cures specific illnesses but does not measurably improve lifespan. Curing all cases of cancer or cardiovascular disease would only add a couple years each to average lifespan.  That’s because we’re still aging, and “your chance of developing a lethal disease increases by a thousandfold between the ages of 20 and 70, so preventing one disease makes little difference to lifespan.”

Instead, we want to modulate our longevity genes to prevent age-related diseases and the effects of aging. Researchers have confirmed we can do this with lifestyle choices. Recent science also suggests certain molecules can achieve the same results. Medicine can mimic the benefits of lifestyle choices.

Live longer without pharmaceuticals

Longevity genes often activate in response to cell stress or damage. Over time, researchers have demonstrated we can activate those genes without actually damaging our cells. Eat less often, exercise more, expose yourself to cold, and avoid harming yourself.

Eat Less Often

Sinclair tells us that, “After twenty-five years of researching aging and having read thousands of scientific papers, if there is one piece of advice I can offer, one surefire way to stay healthy longer, one thing you can do to maximize your lifespan right now, it’s this: eat less often.”

  • Okinawa. Japan’s island of Okinawa is famed for its centenarian population. In 1978, researcher Yasuo Kagawa learned Okinawans eat 20-30% fewer calories than their mainland Japan counterparts. This increased not only lifespan, but healthspan as well, “with significantly less cerebral vascular disease, malignancy, and heart disease.”
  • Biosphere 2. In the early 1990s, this research project took an unexpected twist when the researchers weren’t able to farm enough food to maintain a typical diet. Though not malnourished, team members were often hungry. One resident researcher, Roy Walford, was coincidentally studying the effects of caloric restriction in mice. He observed the same biochemical changes in his roommates that he saw in long-lived calorie-restricted mice: decreased body mass, blood pressure, blood sugar level, and cholesterol levels.
  • Rhesus monkeys. Our close genetic cousins, rhesus monkeys, don’t live past 40. But of twenty monkeys on calorie-restricted diets, six reached 40. This is roughly equivalent to humans reaching 120. However, not all studies show lifespan benefits to calorie restriction.

Intermittent fasting yields similar anti-aging benefits. Sinclair tells us, “Today, human studies are confirming that once-in-a-while calorie restriction can have tremendous health results, even if the times of fasting are quite transient.”

  • Fasting mimicking diet. In 2017, University of Southern California researchers studied a 5-day-per-month restricted diet of vegetable soup, energy bars and supplements. They found the “fasting mimicking diet” improved aging markers and risk-factors: weight loss, reduced body fat and lower blood pressure.
  • Religious fasting. “Blue zones” are regions where people regularly live much longer than average. In Ikaria, Greece, for example, one-third of the population lives past age 90. Most are staunch disciples of the Greek Orthodox church, adhering to many religious fasts. This is anecdotal data, though, and therefore weaker than we’d like.
  • Skipping breakfast. Bama County in China offers more anecdotal longevity linked to intermittent fasting. Sinclair describes centenarians in Bama who skip morning meals, eat a small lunch then a large meal at twilight, “typically spend[ing] sixteen hours or more of each day without eating.”

The contents of our meals also likely impact longevity. For example, “When we substitute animal protein with more plant protein… all-cause mortality falls significantly.” While this evidence is compelling, debate around nutritional science remains.

Tying this back to longevity, calorie restriction inhibits mTOR. When the enzyme is inhibited (by limited availability of amino acids), “it forces cells to spend less energy dividing” and more energy recycling damaged proteins.

Exercise More

Telomeres are like the endcaps of our chromosomes. They shorten as cells divide, creating a sort of countdown clock to genetic instability. Preserving telomeres and mitigating genetic instability therefore leads to longer and healthier lives.

This is where exercise comes in. Researchers found a striking correlation in thousands of adults: those who exercised more had longer telomeres in their blood cells. Intensity matters, too. Researchers at the Mayo Clinic studied the effects of resistance training, high-intensity interval training, and a combination of the two across varying age groups. Sinclair tells us, “it’s high-intensity interval training (HIIT)—the sort that significantly raises your heart and respiration rates—that engages the greatest number of health-promoting genes, and most of them in older exercisers.”

Moreover, Sinclair says, “AMPK, mTOR, and sirtuins are all modulated in the right direction by exercise…,” irrespective of caloric intake.

Cool Off

Newborns start with ample adipose tissue (“brown fat”) on their back and shoulders. Sirtuin-rich, it burns energy and glucose to generate heat but decreases as we age. Luckily, mild cold exposure stimulates brown fat growth. Studies have shown that animals subjected to shivering cold for three hours a day have much more of the mitochondrial, UCP-boosting sirtuin, SITR3, and experience significantly reduced rates of diabetes, obesity, and Alzheimer’s disease.

So, “Exercising in the cold…appears to turbocharge the creation of brown adipose tissue.”

The body of evidence for cold-induced longevity is, however , the weakest among those covered.

Avoid Harm

We manage nutrition, exercise and temperature to modulate longevity genes without damaging DNA. Avoiding undue DNA damage is a key for extending lifespan and healthspan. Therefore, Sinclair recommends we avoid:

  • Smoking
  • Air polluted with DNA damaging chemicals
  • Foods with N-nitroso compounds (cured meats, cooked bacon)
  • Radiation (UV light, X-rays, gamma rays, radon)

Live longer with pharmaceuticals

If Sinclair merely proposed we’ll live longer through lifestyle, Lifespan would be uninspiring. Luckily, Sinclair also offers his unique perspective into the cutting edge of research on molecules that mimic diet, exercise and cold. Research suggests drugs can modulate the body’s longevity genes without causing genetic damage. Of particular interest are  drugs that inhibit TOR, activate AMPK and Sirtuins, or kill off senescent cells.

Rapamycin & Rapalogs (TOR Inhibition)

Rapamycin is an antifungal compound discovered on Easter Island (“Rapa Nui”) in 1972. It’s also an immune system inhibitor. Perhaps most importantly, Rapamycin consistently extends life. It inhibits the TOR pathway, mimicking calorie restriction without any hunger.

It’s been shown to extend the lifespan of yeast cells, fruit flies, and even mice in the final months of their lives by 9-14%. Sinclair says the latter, “translates to about a decade of healthy human life.”

However, “Longer-lived animals might not fare as well on [Rapamycin] as shorter-lived ones do; it’s been shown to be toxic to kidneys at high doses over extended periods of time; and it might suppress the immune system over time.”

Researchers are exploring avenues to mitigate toxicity. Some are testing intermittent Rapamycin dosing with positive results. Hundreds of others, per Sinclair, are “…working in universities and biotech companies to identify ‘rapalogs,’ which are compounds that act on TOR in ways similar to rapamycin but have greater specificity and less toxicity.”

Metformin (AMPK Activation)

Metformin, derived from the French lilac in 1922, is commonly used to treat type 2 diabetes. Recently, though, researchers, “noticed a curious phenomenon: people taking metformin were living notably healthier lives—independent, it seemed, of its effect on diabetes.”

Metformin mimics calorie restriction by slowing cellular conversion of macro-nutrients into energy. This activates AMPK, an enzyme which restores mitochondria and activates sirtuins in response to low energy levels. Sinclair makes metformin’s case with strong language: “In twenty-six studies of rodents treated with metformin, twenty-five showed protection from cancer.” Outside his book, he links to human trials showing metformin reduced the likelihood of dementia, cardiovascular disease, cancer, and more.

Sinclair explains that through AMPK activation, “[Metformin] makes more NAD and turns on sirtuins…engaging the survival circuit.” This slows epigenetic information loss and suppresses metabolism, “so all organs stay younger and healthier.”

STACs (Sirtuin Activating Compounds)

Resveratrol, though discovered in 1939, only came to prominence when a 1997 paper linked it to cancer prevention. Sinclair’s research into Resveratrol’s effects on yeast classified it as the first of many sirtuin activating compounds (STACs). Resveratrol has issues with bioavailability, but other STACs don’t.

NAD, mentioned before, boosts all seven human sirtuins. Our bodies produce NAD from niacin, Vitamin B3. Without NAD as fuel, sirtuins don’t work efficiently.

Sinclair noticed that “NAD levels decrease with age throughout the body.” Since sirtuins require NAD, Sinclair decided to test the effects of boosting NAD. Adding extra copies of the NAD-producing gene to yeast resulted in a 50% longer lifespan. With that knowledge, researchers began seeking molecules to boost NAD without the danger of adding extra genes into humans.

Two molecules have emerged: nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). Sinclair writes, “In the body, NR is converted into NMN, which is then converted into NAD. Give an animal a drink with NR or NMN in it, and the levels of NAD in its body go up about 25 percent over the next couple hours, about the same as if it had been fasting or exercising a great deal.”

Safety studies are ongoing. However, Sinclair asserts, “so far, there has been no toxicity, not even a hint of it.”


When telomeres, our choromonal endcaps, become too short, the cells cannot continue to reproduce. Typically they’ll self-destruct as a form of recycling. Sometimes, though, they’ll become cancerous or senescent instead. 

Think of telomeres as the plastic aglets protecting the shoelace of our chromosomes. Shortened or broken telomeres expose DNA to fraying and damage, triggering cellular repair processes. This can go awry, though. Two incorrectly fused chromosomes can lead to uncontrolled growth: cancer. Alternatively, the sirtuins tasked with DNA repair might not find another end of the DNA shoelace to tie up, permanently shutting down cellular reproduction instead: senescence. The senescent cells no longer grow and divide, but also don’t die, leading some to call them “zombie cells.”

Researchers have found that killing senescent cells has restorative effects in mice, delaying the onset of age-related diseases. Medicines designed to kill zombie cells and delay aging are called, “Senolytics.”

James Kirkland from Mayo Clinic “needed only a quick course of two senolytic molecules—quercetin, which is found in capers, kale, and red onions, and a drug called dasatinib, which is a standard chemotherapy treatment for leukemia—to eliminate the senescent cells in lab mice and extend their lifespan by 36 percent.”

Other Advances

Newer advancements in medical science, not yet rigorously tested and more likely to fail, may also contribute to an increased human healthspan and lifespan. Cellular reprogramming, for example, can turn one type of cell into a completely different type. One such test, though not peer reviewed, restored vision in mice

Precision medicine and DNA sequencing can also help doctors to better understand our bodies and our diseases to prevent misdiagnoses and better tailor treatment options. 

The myriad consumer biometric devices can also help us track our health over time to better inform our choices.

Sinclair’s Conclusion

“Thanks to the technologies I’ve described, a prolonged, healthier human lifespan is inevitable. How and when we’ll achieve it is a bit less certain, although the general path is quite clear. The evidence of the effectiveness of AMPK activators, TOR inhibitors, and sirtuin activators is deep and wide. On top of what we already know about metformin, NAD boosters, rapalogs, and senolytics, every day the odds increase that even more effective molecule or gene therapy will be discovered, as brilliant researchers around the world join the global fight to treat aging, the mother of all diseases.

All of that comes on top of the other innovations that are on track to further lengthen our lives and strengthen our health, such as senolytics and cellular reprogramming. Add to that the power of truly personalized care to keep our bodies running, prevent disease, and get ahead of problems that could be troublesome down the road. That’s not to mention the very easy steps we can all take right now to engage our longevity genes in ways that will provide us with more good years.”

My Conclusion

The current scientific implications are huge. And I believe there’s much more to come. Some paths will certainly dead end. All of them failing, though, seems unlikely. Continued publicity and funding will bring new researchers and fresh ideas, yielding even more interesting pathways to explore.

The idea of living a healthy life past 100 is a possibility, and one I have some control over. Knowing this, I believe it’s time to make the choices to get there. As science fiction writer William Gibson told us, “The future is already here – it’s just not evenly distributed.”

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