by Stephanie Eckelkamp: Everyone gets older and death, of course, is one of the few things we know to be inevitable…
But what many of us also seem to think is inevitable is that with age comes exhaustion, aches and pains, a general lack of vitality, and eventually some type of chronic disease like cancer or Alzheimer’s. I can’t tell you how many times I’ve half-joked that my crunching knees and occasionally crippling fatigue exist because I’m now in my 30s.
Slowly but surely, however, the whole idea of aging is being flipped on its head. Given breakthroughs in research that have led to new understandings of what drives the aging process on a molecular and cellular level, more scientists than ever are saying, hey, maybe we don’t actually have to age—at least not nearly as quickly or painfully as we do now. Maybe we can strategically target the underlying mechanisms of aging in a way that adds years to our lives (we’re talking beyond 100) and makes those years truly worth living.
That’s the goal, at least, of Harvard geneticist David Sinclair, Ph.D., who is perhaps the most outspoken proponent of this emerging idea that aging itself should be classified as a disease that can, in fact, be treated.
“What if I told you that you could be just as happy, healthy, and satisfied as you are today at age 120?” Sinclair asked a group of Google employees in September of 2019 while giving a talk about his research and new book Lifespan: Why We Age—and Why We Don’t Have To. “We have the technologies to be able to be healthy much, much longer until later in life. The hope is that our generations will be able to expect to live until 90 and play tennis, or even make it to 100 and have a career—a second, third, or fourth career.”
Pretty enticing stuff, right? And while part of what Sinclair is referring to when he speaks of these “technologies” is medications and genetic therapies that are being tested for their life-extending, disease-preventing (and possibly disease-reversing) potential, his research—and that of other experts in the field—has also uncovered key lifestyle practices and nutrients that target these same longevity pathways in the body. Things that all of us, right now, can tap into.
So let’s unpack some of this, shall we? Here, we dive into the latest research on what actually drives aging on the micro-level, the innovations we may be seeing in the near future, and what functional docs, and Sinclair, believe to be the best habits to adopt for a long, healthy life.
So what is aging & what drives it on a cellular level?
Right now you might find yourself asking, what exactly is aging? Sure, you may associate it with disease and frailty, but what exactly is it that makes someone more likely to lose muscle mass, experience significant declines in energy, and get cancer at age 70 rather than at age 25? It seems like it should be a simple explanation, but it’s pretty darn complex—and experts’ views on what drives aging have changed quite a bit over the years.
“In simplest terms, aging is wear and tear—you do something over and over again and the parts break down,” says Robert Rountree, M.D., renowned integrative medicine physician who makes a point to stay on top of new aging research. “Additionally, there are a lot of bad proteins being made in our cells all the time; there’s a lot of debris generated—but when we’re younger, we have the ability to compensate for the ‘mistakes.’ So basically, there are mistakes and there is damage, and as we get older, the factories in our cells make more mistakes and are less able to recover from damage.”
But what’s causing these mistakes and this damage? Back in the day—we’re talking from the 1950s up until the 1980s—the free radical theory of aging dominated. Originally described by Denham Harman, the theory states that organisms age because they accumulate oxidative damage caused by reactive oxygen species, or free radicals. These free radicals would supposedly damage DNA, damage proteins, and basically wreak havoc throughout the body. “So if you follow that theory, you’d think that you’d want to take as many antioxidants like vitamins C and E, zinc, and selenium as possible and that would keep you from aging,” says Rountree. “Except when [researchers] did that in animal studies, it didn’t work.”
So, what do we think now? In the past decade or so, scientists have settled on nine “hallmarks,” or causes, of aging, says Sinclair, although this list will likely evolve in the future. And the idea is that if we can address these issues, we can slow aging, prevent disease, and add healthy years to a person’s life. These hallmarks include:
- Genomic instability caused by DNA damage
- Wearing away of the protective chromosomal end caps, or telomeres
- Alterations to the epigenome that controls which genes are turned on and off
- Loss of healthy protein maintenance, known as proteostasis
- Deregulated nutrient sensing caused by metabolic changes
- Mitochondrial dysfunction
- Accumulation of senescent zombielike cells that inflame healthy cells
- Exhaustion of stem cells
- Altered intercellular communication and the production of inflammatory molecules
We’re not going to dive into all of these, but let’s cover a couple that have been getting some extra attention lately: senescent cells, for example. Turns out, there’s a limit to the number of times a cell can reproduce, called the Hayflick limit. When cells reach this limit, they’re called senescent. “We used to think, well, they’re old and in the way, but they’re harmless,” says Rountree. “But it turns out, they’re releasing harmful signals and inflammation to the body.”
Another topic you’ve likely read about right here on mbg is mitochondrial dysfunction. Think back to high school biology class—mitochondria are the powerhouses of our cells, which produce ATP or energy. “When we get older, we tend to lose mitochondria because mitochondria don’t have the same kind of repair mechanisms as our DNA,” says Rountree. “So over time, we get more tired and we don’t have the energy to fuel our cellular mechanisms.”
But—and here’s where things get a little crazy—Sinclair believes there could be one common driver of all nine of these processes, which he sums up with his information theory of aging. “The theory proposes that all of the causes of aging that people are working on—from loss of mitochondria to senescent cells to telomere shortening—are manifestations of a very simple principle, which is a loss of epigenetic information in the cell rather than genetic information. Meaning that cells lose their ability to read the right genes at the right time, in the same ways that scratches on a CD would mess up the ability to play a beautiful album,” he says. (The epigenome, if you’re unfamiliar, essentially tells the genome what to do.)
“What I’m proposing,” he says, “is that if we can stop the epigenome from degrading, all of these other things go away.” But if Sinclair’s new theory is true, it raises the question: How the heck do you prevent these scratches (aka epigenome degradation) so cells continue to read the right genes at the right time, and so you can avoid things like fatigue, frailty, and cancer? And can we “clean up” damage that’s already there and essentially turn back the clock?
According to Sinclair, there are sort of two levels to that answer. One, there seems to be quite a bit we can do that may effectively slow the aging process (i.e., prevent these scratches) via targeted dietary and lifestyle changes and a few promising supplements, which we’ll dive into in the section below.* As for the second part of the question, to truly turn back the clock, lifestyle changes won’t cut it. But future therapies and drugs could make that possible.
“We think we’ve figured out how to reset the age of cells,” says Sinclair. “We’ve figured out that there’s essentially a backup hard drive with this epigenetic information that we can access and tell the cells to be young again and reset their clock.” Sinclair admits that this work is still quite preliminary, but they’ve just had some very promising results in animal studies with gene therapy treatments (right now they’re injections, but they could eventually be pills). In a study from July 2019, they were able to reprogram damaged optic nerve cells in mice with glaucoma and restore vision.
“That’s another level of science that’s coming, and we’re still in the early stages, but if we can restore vision, what else might we be able to reset?” he asks. Which, to be honest, is equal parts freaky and fascinating.
Key pathways in the body regulate aging—and we’re figuring out how to tweak them with lifestyle changes.
Stepping back from the crazy sci-fi “making blind mice see” stuff for a sec…some of the recent longevity and aging research has shed light on how we can effectively slow aging with targeted lifestyle changes, as alluded to above. Scientists are now learning that by activating certain longevity genes and pathways in the body, we may be able to slow down the aging process and make sure those epigenetic scratches Sinclair speaks of don’t accumulate very quickly.
“These genes are activated by how we live our life,” says Sinclair. “Whether we’re doing intermittent fasting or exercising or eating the right foods, what we now know is that the reason these habits keep us healthy is because they’re turning on these longevity genetic pathways that defend us against diseases of aging, and aging itself.”
But first, what are these genes and pathways? Sinclair says scientists have figured out that there are three main pathways considered “universal regulators of aging” that are present in all sorts of organisms—from yeast to worms to mice to humans—which respond to things like what and how much we eat, and how we exercise. “They sense different things in the body, but they talk to each other,” says Sinclair. “So if you tweak one, the other two will follow. That’s why they seem to do very similar things.” Here, a brief rundown:
- Sirtuins: These are a set of seven enzymes (SIRT1 to SIRT 7) that Sinclair has played a pivotal role in researching. In mouse studies, activating sirtuins has been shown to promote DNA repair, promote the formation of mitochondria, extend telomeres, enhance memory and endurance, promote the cellular “cleanup” process known as autophagy, and help mice stay thin. All sirtuins require a molecule called nicotinamide adenine dinucleotide (NAD). Levels of NAD, however, naturally decline with age (and they’ll decline even faster if you’re overweight or obese, says Sinclair), resulting in a decline in sirtuin activity that experts believe is a big reason for increased disease risk when we’re older.
- AMPK: AMP-activated protein kinase (AMPK) is a metabolic control enzyme that senses the amount of energy in a cell and then balances nutrient supply with energy demand. When the AMPK pathway is activated (through, say, fasting), it promotes autophagy, helps form new mitochondria, reduces inflammation, improves insulin sensitivity, and more. AMPK activity has also been shown to decline with age, which is why taking steps to support it is key.
- mTOR: Mammalian target of rapamycin (mTOR) is a pathway that responds to the amount of amino acids, or protein, you’re eating. When you eat protein, mTOR is activated and promotes protein synthesis and cell growth. To some extent, this is beneficial; however, when you overconsume protein, mTOR prioritizes short-term growth over long-term survival by shutting down longevity pathways. Inhibiting mTOR, on the other hand, has been shown to be beneficial for longevity, promote DNA repair, reduce inflammation caused by senescent cells, promote autophagy, and more.
These, of course, aren’t the only pathways associated with longer life. They’re just the ones Sinclair is particularly obsessed with. When I asked Rountree for his take, he agreed that these are quite important, but in his opinion, “The No. 1 cellular pathway that’s involved in aging is called the insulin-signaling pathway,” says Rountree. “What does that say? It says that blood sugar regulation is really at the core of the aging process.”
In fact, the hormone insulin-like growth factor 1 (IGF-1), which increases with the consumption of refined carbs as well as protein, and which is a biomarker for cancer, has been closely tied to longevity. Research by Nir Barzilai, Ph.D., and others at Albert Einstein College of Medicine has found a very strong association between low IGF-1 levels and increased lifespan in some of the world’s longest-living people. High IGF-1 levels, on the other hand, have also been found to have negative effects such as inhibiting autophagy.
If you’re unfamiliar with autophagy, it refers to a “self-eating” process by which cells disassemble and clean out unnecessary or dysfunctional components—organelles, proteins, and debris that are no longer efficient. Autophagy also encompasses mitophagy, the removal of damaged mitochondria. According to holistic neurologist Ilene Ruhoy, M.D., most age-related neurodegenerative disorders like Alzheimer’s are associated with the accumulation of misfolded proteins or pathologic proteins—so impaired autophagy likely contributes to these diseases.
So, how exactly can we target these pathways with our daily habits and (hopefully) slow aging?
The good news: Science is revealing that most of them are influenced by similar lifestyle habits and nutrients—and there are even some supplements that seem to live up to the hype.*
1. Periodically “stressing out” your body seems to be key.
The two biggest lifestyle activators of the aforementioned longevity pathways are fasting (or time-restricted eating) and exercise, says Sinclair. What do they have in common? They’re hormetic (or pulsatile) stressors, which put the body into a state of perceived adversity called hormesis.
There’s also some research to suggest that heat exposure and cold exposure (think saunas and cold plunges) are also hormetic stressors that activate these pathways. Both have been associated with mitochondrial biogenesis, and sauna use has even been associated with reduced all-cause mortality risk. More research is needed in this area, but it’s compelling enough that functional medicine physician Frank Lipman, M.D., finishes off his showers with a blast of cold water, and aging expert Rhonda Patrick, Ph.D., regularly hits the sauna.
During these perceived states of adversity—whether that’s nutrient adversity from narrowing your eating window or oxygen depletion in your muscles after a HIIT workout—longevity pathways are either activated or inhibited in a way that tells cells to hunker down and to prioritize the recycling and repair (via autophagy and other mechanisms) over division and growth. This may sound weird, but as we age, we actually don’t want to promote growth as much as when we were kids and adolescents—that’s because the same things that promote the growth of healthy new cells also promote the growth of things like cancers, which become more likely when we’re older and our cells make more mistakes.
So, what type of exercise and what type of fasting seems to be optimal for longevity? With exercise, most experts agree that you need a minimum of 150 minutes a week (about 21 minutes a day) of something that gets your heart pumping, says Rountree. As for the specific type, try switching things up and doing workouts of different intensities that target different muscles. A recent 2019 study in humans found that both aerobic and resistance exercise increased levels of a NAD-precursor called NAMPT, ultimately leading to more NAD, which activates sirtuins.
With fasting, there’s a little more debate—but you likely don’t need to go to extremes to reap the benefits. Sinclair tends to stick to two meals a day, Ruhoy confines her eating to a 10-hour window shifted toward the beginning of the day (from 8 a.m. to 6 p.m.) to promote quality sleep and optimal circadian rhythms, and Valter Longo, Ph.D., director of the USC Longevity Institute, suggests sticking to a very reasonable 12-hour eating, 12-hour fasting window, or scaling back to two meals a day plus a snack if you’re overweight or obese.
“It’s really the way lots of centenarians and people who live a long life have always done it,” Longo says. Extending your fast to 16 or 18 hours a day, however, may have short-term benefits, but we just don’t know enough about the long-term safety to make them a widespread recommendation, says Longo, who cites potential risks like gallstones.
Longo has also developed a fasting-mimicking diet (FMD), which he created to deliver the benefits of caloric restriction without the risks. This very low-calorie plan, which consists of mainly plant-based foods and plenty of good fats, is meant to be done in five-day stretches (up to three times a year) and has been shown in studies to aid in weight loss, reduce body fat and blood pressure, and reduce levels of IGF-1. Not only does this type of diet promote autophagy, but research suggests it could make cancer cells more vulnerable to treatment.
2. Neither too much nor too little protein is a good thing.
As we briefly mentioned above, consuming too many amino acids (or proteins) may not be a good thing for optimizing longevity, as it ramps up the growth pathways mTOR and IGF-1 and inhibits processes like autophagy and apoptosis (cancer cell death). This is why some longevity experts promote a lower protein diet, particularly lower in animal protein.
Longo recommends lowering protein intake to the lowest amount that’s still considered sufficient by medical associations, or the recommended daily allowance (RDA)—about 0.35 grams of protein per pound of body weight (if someone weighs 150 pounds, that’s 53 grams), and up to 0.45 grams per pound if you’re over age 65 to counter age-related muscle loss.
However, it’s also important to note that IGF-1 and mTOR play beneficial roles in the body, including growing and repairing muscles and even promoting the growth of neurons. So you do need some protein—and that amount can likely bump up a bit from Longo’s recommendation if you’re prioritizing physical activity and you lead an overall healthy lifestyle.
“There have been studies showing that higher protein intake does increase all-cause mortality and cancer mortality,” said Patrick in a recent video post. “However, people who had higher protein intake but none of the unhealthy lifestyle factors—for example, they’re not obese, they are physically active, they don’t smoke, they’re not drinking excessive alcohol—actually had the same mortality rate as someone who had a lower protein intake.”
So basically, if you’re going to be giving your body extra fuel in the form of protein, use it. In fact, even Sinclair—who says that he generally tries to avoid eating mammals—still eats meat if he works out.
3. Certain nutritional supplements actually seem to work.*
Sinclair’s work from the early 2000s was the first to reveal that resveratrol (a compound found in red wine and grapes) influences sirtuins in a similar way to fasting.* And while resveratrol supplements have sort of fallen off the radar of late, Sinclair still takes 1 gram every morning stirred into his homemade yogurt. “There’s been a lot of hype around it, but that hasn’t diminished my enthusiasm for it as a supplement,” he says. “In fact, the more we learn, the more interesting it gets.”
There’s also another class of supplements that’s starting to generate a lot of buzz and has a fair amount of research to back it up: NAD precursors, which include nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). These molecules are converted into NAD in the body. In case you forgot: NAD is the molecule we discussed above that’s crucial for activating sirtuin longevity genes, but that naturally declines with age.*
Both Rountree and Ruhoy think these NAD precursors are pretty exciting. “I think overall we’ve gotten a little supplement-happy, but there are a few I think are very useful, and NR is one of them, without question,” says Ruhoy. “It helps to support mitochondrial function, and it’s incredibly important in autophagy, and I recommend it fairly regularly.”*
At this point, there’s been much more research on NR, which has been shown to support muscle strength and mitochondrial functioning, among other things.*
Additionally, resveratrol and NAD seem to have a synergistic relationship—”resveratrol is like the accelerator pedal for the sirtuin enzymes, while NAD is the fuel,” says Sinclair. So resveratrol and NAD precursors may work well together.*
4. Eating a variety of colorful plants and prioritizing sleep are still nonnegotiables.
Even though Sinclair loves to rave about the latest in healthy aging technology, he says some of the most basic health recommendations can have the biggest impact. One thing he tries to always have on his plate: colorful vegetables and fruits. Sinclair ties their benefit to something you’ve probably never heard of: xenohormesis—the idea that stressed plants produce chemicals (in the form of colorful plant pigments, like resveratrol) that tell their cells to hunker down and survive. And then, when we eat these plants, we get the benefits too.
In fact, in a somewhat controversial view, he believes many of the compounds in plants that were thought to be beneficial due to their antioxidant properties are actually beneficial due to their ability to tweak our genetic survival pathways. Regardless of how they work, however, you should be eating more of them.
Getting plenty of sleep is also key, especially for brain health. “Restorative sleep is super important because that’s when the lymphatic system is most active and sort of rids the brain of all the debris from all the metabolism that goes on all day and night,” says Ruhoy. It’s also when most autophagy in the brain occurs. Aim to go to bed and wake up at the same time every day, suggests Ruhoy—and even aim to eat on a consistent schedule. We’re circadian beings, and our bodies and brains thrive on a rhythm.
So why exactly do some experts want to classify (and treat) aging as a disease?
Sinclair’s research on resveratrol is what first triggered the idea that developing a drug to slow aging wasn’t crazy. Since then, scientists have been working on testing the anti-aging potential of existing drugs like metformin (the widely prescribed diabetes drug that activates AMPK and has been shown to have preventive effects for multiple chronic diseases) as well as developing and testing new molecules that target longevity pathways and could one day be prescribed specifically for aging—not just age-related diseases.
Because aging isn’t currently classified as a disease, though, progress isn’t moving as quickly as Sinclair would like. “If aging is classified as a disease or disorder, then drugs will be developed directly to prevent and treat aging, and also investment will go up dramatically,” he says. “And that’s what we need for this field to move forward more quickly.”
How likely is that to happen? It’s definitely not a far-fetched idea. Barzilai and his colleagues at the Albert Einstein College of Medicine are currently studying the anti-aging effects of metformin in the Targeting Aging With Metformin (TAME) study, and if they can show significant benefits in delaying problems such as cancer, dementia, stroke, and heart attacks, the FDA may consider classifying aging as a treatable condition.
But even though that hasn’t happened yet, there’s still a huge biotech industry working on aging right now. “There are dozens of companies working on different aspects of aging. From a company working on autophagy to one that deletes senescent cells to a company working on stem cell boosters, pretty much every aspect of aging is being covered,” says Sinclair. “And many of them are in clinical trials—so it’s not a question of if these drugs will hit the market; it’s a question of when.”
Initially, until aging is classified as a disease, these drugs will need to be developed for specific conditions, says Sinclair. But eventually, he’d want to make them available to everyone.
While Sinclair is pretty gung-ho, Longo views the new frontier of aging drugs as an area that’s both promising and potentially dangerous. “If we can target these master regulator pathways, that could have very beneficial effects,” he says. “But as with all drugs, you’re interfering with something, and there’s the potential for it to backfire.”
“Of course, with many drugs, the benefits outweigh the risks—if someone has a systolic blood pressure of 200, they’re at very high risk for cardiovascular disease, so you don’t really have a choice but to put them on blood pressure medication,” he says. “But with aging, what makes this tough is that there’s no acceptable risk. You can’t say, well, 1 in 1,000 people are going to die young because the other 999 now get to live until 95 instead of 90. That’s what I think some of my colleagues are underestimating: that nobody gets to be left behind in this anti-aging world.”
Oddly enough, research into drugs could help us determine the most effective, natural supplements.
If you’re of the natural, holistic mindset, and the idea of taking metformin or another drug to combat “aging” seems a little…freaky, we get it. But some experts feel that the advances made in this field could actually lead to advances in the supplement world by helping us home in on natural compounds that have similar characteristics to these drugs.
“What I’ve always done in my practice is I look at what the pharmaceutical companies are talking about, what they’re doing, then I reverse engineer that to supplements,” says Rountree, who also serves as the chief medical advisor to Thorne. “Then I go, OK, this is a pathway we really need to pay attention to? Is there any research that any herbs or nutrients affect it? There’s research on Rhodiola rosea, for example, which appears to inhibit the mTOR pathway, so that’s one that I like a lot.* I also take berberine, which works by modulating some of these nutrient-sensor pathways like AMPK, so it’s kind of a natural mimic of metformin.”
Rountree also believes we’ll get more answers by studying people who have managed to live past 100 and maintain pretty good health, to see what’s happening on a molecular level. “Maybe you don’t have the same genes as that person, but maybe you could reproduce the effect by taking a certain amount of resveratrol or NR.* I’m not saying those two are going to be the answer, but I feel like we’re finally in a place where we’re learning to ask the right questions. It’s exciting to think we may be in a place in the very near future where we can tell somebody, with a fair amount of certainty, here is a menu of nutrients you can take that will add years to your life.”*
Bottom line: You should feel empowered.
Clearly, if you’re interested in staying on this planet as long as possible (and feeling pretty good while you’re here), it’s an exciting time to be alive. And while it’s easy to get caught up in the hype of “miracle aging drugs” and genetic therapies that could reverse blindness, the truth is, a lot of this aging research has either confirmed or helped us subtly tweak many of the recommendations functional and integrative medicine physicians have been making for years or led us to discover new, relatively simple lifestyle tweaks to improve our health.
So move your body, allow yourself to get a little hungry now and then, load up on veggies and don’t overconsume protein, get plenty of sleep, consider having a nice little meditation session in a sauna now and then, and maybe try a new supplement under the guidance of your doctor.*
“Don’t get caught up in this belief that we’re going to find a magic pill,” said Lipman at this year’s mbg revitalize conference. “The ordinary things we do on a daily basis have extraordinary healing effects; don’t take those for granted.”
