by TC Luoma
The Science of Longevity and Mimetics
Does the eat-big-train-hard lifestyle shorten your lifespan? That's what some people say. Here are the facts.
A T Nation reader threw me a curveball a couple of days ago. He sent me a long email that made the case that weightlifting and the weightlifting lifestyle are incompatible with living a long time.
He made several intriguing points, many of which have been made before by longevity specialists. He noted that super centenarians (the infinitesimally small percentage of people who live to be 110) don’t eat very much and have little muscle mass. He also noted that they’re all united in that they have low-protein diets that are, if not totally vegetarian, then “almost vegetarian.”
He also pointed out that while these super centenarians are certainly active, their efforts don’t extend much beyond walking and gardening; certainly not anything that involves a bench press.
Based on these observations, he came up with some bitter rules for fitness enthusiasts to live by, at least if they want to live a long time:
- Reduce your protein intake. Restrict most protein intake to just before workouts. Avoid those protein pulses you’ve been having during the day “just to build muscle.”
- Stop training intensely. Higher frequency and perhaps higher volume are okay, but stop the strongman lifts.
- Start fasting. Try to identify a 12-hour period where you don’t eat at all. Maybe do 5 days of “quasi-fasting” every couple of months.
- Work out after you eat, but not before. Ideally, time your workout to be immediately after your largest meals. This provides a number of benefits ranging from glucose management to nutrient partitioning.
- Ditch the post-workout meal. In fact, ditch any meal you can that’s not close to a workout.
So, how does all that strike you? Are you feeling dejected? Ready to trade your belt, chalk, and weightlifting straps for a floppy hat, a sack of manure, and some gardening tools?
Or are you one of those live-for-today guys who will – if contrarian boy is right – keep on slowly killing yourself with heavy weights, vigorous exercise, and lots of protein because you’d rather die young and purty than old, wrinkled, and smelling like bad cheese?
Well, relax. I don’t think you really need to rethink your lifestyle all that much. While the aforementioned troublemaker of a reader made some thought-worthy observations, many were made without taking a bunch of other underlying facts into consideration, including some new breakthroughs in the area of calorie-restriction mimetics (more on that later).
He was also mildly guilty of a couple of post hoc fallacies, which is an even snootier way of saying correlation does not equal causation. Let’s say, for the sake of argument, I wrote an article wearing nothing but Care Bear underwear and didn’t make a single typo. Based on that success, I then decided to wear nothing but Care Bear underwear every time I write an article.
Now, they may be comfortable, they may be whimsical, and they may even be alluring to the right kind of woman, but the Care Bear underwear aren’t magic; they had nothing to do with me not making any typos.
I think this type of logical fallacy comes into play in our unnamed reader’s first point about how the long life of super centenarians (and probably old people in general) has to do with having little muscle mass, eating very little protein, and engaging in very little strenuous exercise.
Does Too Much Protein Lead to an Early Death?
Before age 65, eating lots of protein does indeed correlate with early death, but we need to look closer at what that means. When most people eat protein, it’s eaten as animal tissue, often fatty animal tissue, often processed animal tissue, often deep-fried, charred to the bone, or coated with cheesy pasta-sauce animal tissue.
In other words, that animal protein comes loaded with advanced glycation products (harmful chemicals caused by the joining of protein with sugar), loads of cancer-causing nitrates, and tons of saturated and “unbalanced” fats (fats that have their omega-6 to omega-3 ratios all out of whack).
Most people are NOT getting all their protein from steamed fish or highly purified protein powders from either plant or animal sources, so yeah, it makes sense that mortality rates might be higher among this generic type of protein eater.
A funny thing happens, though, when people hit 65; protein has an inverse relationship with death. Codgers who eat more protein generally live longer. So what exactly is happening here? Lots of things.
When people get older, they lose their appetite for protein and food in general. Older people often have poor appetite, don’t digest and process proteins very well, have dental issues or trouble swallowing, are often trying to fight off some sort of malady, and quite possibly vastly underestimate their protein intake.
This is potentially a problem because so much, aside from just muscle, depends on protein. The hormones and enzymes that regulate most of your bodily functions are made of protein. Proteins comprise antibodies and they also transmit signals between different cells, tissues, and organs. On a larger scale, they form the scaffolding upon which cellular constituents are built.
The cells in your body couldn’t even move without actin, a protein involved in contraction of muscle cells, cell locomotion, and even cell division. And none of the preceding takes into account that your body needs protein to regenerate the billions of cells that are constantly dying.
Protein isn’t stored and if it isn’t provided through the diet, the body starts stealing it from the muscles. The protein-deficient body gets weaker and weaker and this is exactly what’s happening in a lot of old people.
A 2017 study found that old people who consumed the least amount of protein were almost twice as likely to have trouble walking or climbing stairs as those who ate the most (Mendonca, et al.). Another study done in 2018 had similar findings (Hruby, et al.).
Carry out this loss of muscle to its logical conclusion and you can imagine falls and broken hips and living out the rest of their lives being painfully jostled between wheelchairs and beds. Often, that lack of mobility further weakens the body and sets the stage for infections and diseases for which there are no recovery. Mental functions fail, too. Healing slows. And death comes early.
So yeah, having EXTRA protein should, in general, help old people live longer. But what about all those advanced glycation products and cancer-causing chemicals I described? Well, they’re still a factor, but, after 65 (or so), the benefits of eating more protein probably outweigh the dangers.
Being oldsters, the super centenarians described above don’t eat or even absorb much protein, so they’ve lost a lot of muscle mass. Resistance exercise might have made a difference, but it probably isn’t necessary for their longevity. Exercise of some kind appears to be an essential component, though, and most of these ultra old people seem to still be active.
And yes, getting most of your protein from vegetarian sources would indeed eliminate many of the problems associated with conventional animal proteins, so I’ll concede that point.
But why else then do these super centenarians live longer? It likely has to do with three important things: calorie restriction, glucose management, and a lucky genetic draw that gives them mitochondrial density, which leads to lower levels of “free radical leakage.”
The Magic of Calorie Restriction
Calorie restriction (CR) is the chronic reduction of total calorie intake without malnutrition. It’s the one thing that’s pretty much universally thought to increase life span in round worms, rodents, and presumably humans, too.
Its effects are many, but chief among them is the activation of SIRT proteins, but primarily SIRT1, an intracellular regulatory protein that plays a big role in obesity-associated metabolic diseases (including insulin sensitivity), cancer, adipose tissue, aging in general, cellular senescence, cardiac aging and stress, prion-mediated neurodegeneration, and inflammatory signaling in response to environmental stress.
To get specific, SIRT1, courtesy of calorie restriction or even fasting, also induces systemic autophagy, which is a process by which the body takes out cellular trash. Cells get old. Their proteins gunk up and they build up unwanted, harmful molecules so they need to be purged by the aforementioned autophagy, which is ancient Greek for “self-eating.”
SIRT1 also affects something called “cellular uncoupling,” which is the disassociation of the electron flow from the production of ATP in the mitochondria, which restricts the leakage of free radicals.
If these free radicals were allowed to run rampant, they would lead to the release of cytochrome C into the cellular fluid, which sets into motion a cascade of enzymes that slice up and dispose of the cell (apoptosis). Do that enough times and you slice up an entire organ. Slice up enough organs and you’re put in a home, a box, or an urn.
So SIRT1 is good. But if you completely shut off or slow down free radical production too much through external methods like an antioxidant diet or drugs, the membrane potential of the mitochondria collapses and it spills apoptotic proteins into the cell. If a larger number of mitochondria do this, the cell dies. If a large number of cells do this, the organ and overall health of the individual is affected.
In the case of controlling free radicals, it seems you’re damned if you do and damned if you don’t, but CR puts into play mechanisms that fine-tune free radical production.
Let’s consider those super centenarians. In addition to most of them following a CR diet, it appears that many, if not all of them, have a gene that leads to a tiny reduction in free radical leakage. If you have this gene, you’re 50% more likely to live to be a hundred. You’re also half as likely to end up in a hospital for any reason.
You can see that CR is a hugely compelling concept, at least if you want to live a long, healthy life. Having longevity genes is better than practicing CR, but hey, you work with what you’ve got.
As far as calorie restriction, we can “do” CR without actually eating the diet of an underweight chipmunk. As our unnamed email writer suggested, there’s evidence to suggest that intermittent fasting (IF) can accomplish some of the same things as full-time CR. This IF could take the form of the 8-16 hour eating protocols many people follow, or even doing a session of CR every few weeks might be enough.
But here’s another place where our email writer’s argument falls apart. There’s no need to practice full or part-time CR to live a long time because there are also plenty of drug and supplements that act as calorie restriction “mimetics” in that they, too, increase SIRT1 activity, in addition to just plain extending lifespan and/or “healthspan” in model organisms, i.e., lab rats or some other type of hapless organism.
The Calorie-Restriction Mimetics
While there are a number of potential calorie restriction mimetics (CRMs), only a dozen or so are known to induce SIRT1-like effect that result in protective autophagy and other health-promoting effects. Among them are:
Resveratrol
This polyphenol, primarily found in grape skin, targets AMPK and SIRT1, both of which can recreate some of the metabolic changes of CR in humans. Specifically, resveratrol has been shown to have protective effects against metabolic syndrome, type 2 diabetes, cancer, neurodegeneration, and cardiovascular disease.
And, more pertinent to our conversation, resveratrol has been shown to promote longevity across species.
Spermidine
This polyamine is naturally produced in the body as well as by intestinal microorganisms. It’s also found in wheat germ, soybeans, and various nuts. Spermidine supplementation has also been shown to increase lifespan across species, suppress tumor growth, beef up anti-cancer immune responses, stimulate T cell formation, protect the heart, and improve skeletal muscle regeneration.
Moreover, increased levels of spermidine in the blood have been linked to longevity in healthy nonagenarians and centenarians.
Aspirin
Although it’s often implicated in gastrointestinal bleeding, the potential benefits might outweigh that risk because aspirin, in general, has shown mortality-reducing effects in several human studies. It’s even been proposed as an anti-cancer therapeutic.
Continuous use of aspirin has resulted in lower tumor occurrence and decreased metastasis of colorectal, breast, and prostate cancers, probably as result of its activation of AMP-activation protein kinase (AMPK) and the aforementioned process of autophagy.
Metformin
This drug, a derivative of compounds found in French lilac, is a widely prescribed drug for the treatment of type 2 diabetes. It’s also thought to be the first true longevity drug in that its been shown to be beneficial against a host of age-related diseases including cancer, metabolic disorders, cardiovascular disease, and cognitive dysfunction.
It’s thought that metformin directly impacts SIRT1 gene expression, solidifying its standing as a true CRM.
Polyphenols in General
Several of these plant compounds are legitimate CRMs or qualify as potential CRMs. Caffeic acid, found in black tea and several other plants, for one, reportedly activates AMPK and induces autophagy. Piceatannol, a stilbenoid found in passion fruit, has been shown to activate SIRT1.
Catechin and epicatechin, found in cocoa and red wine, induce autophagy, while epigallocatechin (EGCG), found in green tea, activates SIRT1.
Curcumin, famous for numerous positive effects on human health, activates AMPK and induces autophagy. Likewise, cyanidin 3-glucoside, while not yet traditionally regarded as a CRM, deserves inclusion because of its remarkable similarity in action to metformin.
Manage that Glucose!
Another thing that modern-day Methuselahs have in common is that they remain sensitive to insulin throughout their life. In other words, their bodies manage blood sugar quite well. That means they accrue fewer of the advanced glycation end products that promote aging.
Their enviable sensitivity is likely a byproduct of good genes and their calorie restriction diet, but there are ways to duplicate these effects. Simply exercising regularly, especially with resistance exercise, works wonders because the bigger your muscles are, the better they dispose of glucose.
Secondly, there are plenty of nutritional strategies to facilitate glucose disposal. We might use high-quality fish oil, or take cyandin 3-glucoside. We might take cinnamon, apple cider vinegar, or psyllium once a day. Taking a walk after dinner helps, too.
Get Those Mitochondria Healthier and Denser in Number
One thing all the oldsters universally enjoy is mitochondrial health and probably increased mitochondrial density. As explained, having few or dysfunctional mitochondria ultimately leads to premature cell death, which ultimately leads to premature organ senescence. Knock enough organs out of commission and you’re dead.
The mitochondrial health and density of the old folks probably isn’t solely due to calorie restriction, but also from a lucky draw in the genetics department. Nevertheless, regular people can make up for unlucky genetics by exercising a lot, which increases mitochondrial density.
They can also use supplements like pyrroloquinoline quinone, or PQQ, which is one of the few compounds that causes the formation of new mitochondria. Other mitochondria friendly compounds include coenzyme Q10, creatine, resveratrol, and Vitamin D.
How to Live Long Enough to Get All Wrinkly
The fitness lifestyle typically doesn’t involve chronic calorie restriction or the avoidance of strenuous exercise. However, we can likely approximate many of the health advantages seen in long-lived individuals, including centegenarians, by adopting some lifestyle modifications and some nutritional strategies.
(I say “likely,” because we won’t quite know until enough of us fitness types die and give epidemiologists and other like-minded scientists a large enough sample size.)
Most people who are reading this already have the lifestyle modifications in place. Exercise, especially cardio, increases mitochondrial density, while exercise in general, but especially resistance exercise, leads to better glucose management.
Many of you also undertake occasional bouts of intermittent fasting, which probably conveys many of the same benefits of a chronic calorie restriction diet.
Supplements are also a vital component as they too can increase mitochondrial health and density and improve glucose sensitivity while also acting as calorie restriction mimetics.
Below is my personal longevity “formula.” It could easily have been longer, but I managed to shorten it a bit by choosing some compounds that had pleiotropic properties, i.e., supplements that had multiple life-extending effects, or supplements that affected other biological pathways.
For instance, resveratrol “feeds” mitochondria, targets AMPK and SIRT1, and acts as an aromatase inhibitor (reduces estrogen levels), so more bang for my buck. Anyhow, here’s the list:
- Aspirin (Buy at Amazon) – 1 to 2 baby aspirin a day (if you weigh under 150 pounds, 1 tablet; if you’re over 150, 2).
- Creatine – 5 grams a day
- Curcumin (Buy at Amazon) – About 800 mg. a day, in two divided doses.
- Cyanidin 3-glucoside (Buy at Amazon) – 400 to 600 mg. a day, a half-hour before meals.
- PQQ (Buy at Amazon) – 20 mg. daily – One capsule a day (this is a nice formula because it also contains Coenzyme Q10, which also supports mitochondrial function).
- Resveratrol (Buy at Amazon) – 600 mg. a day.
- Superfood (Buy at Amazon) – This product contains 18 freeze-dried fruits and vegetables that contain a ridiculously rich bounty of polyphenols. 1 to 2 servings a day.
- Vitamin D (Buy at Amazon) – 5000iu a day.
Obviously, plenty of things other than calorie restriction, glucose management, or mitochondrial density play a role in living a long, healthy life. Good nutrition in general is of course important, as is a healthy and robust immune system and a lack of any genetic predispositions to specific illnesses. So is the avoidance of speeding buses and not taking a job as an Alaskan crab fisherman, but you knew all that.
The important thing, at least as it relates to this article, is not to second-guess your fitness lifestyle – at least not based on what we know today. Tomorrow may bring new findings and new theories, but we can worry about them then.
References
References
- Hruby A et al. Protein Intake and Functional Integrity in Aging: The Framingham Heart Study Offspring. J Gerontol A Biol Sci Med Sci. 2020 Jan 1;75(1):123-130.
- Madeo F et al. Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. Cell Metab. 2019 Mar 5;29(3):592-610.
- Mendonca N et al. “Protein Intake and Disability Trajectories in Very Old Adults: The Newcastle 85+ Study.” Journal of the American Geriatrics Society, 01 November 2018.
- F. Pietrocola, et al. “Aspirin Recapitulates Features of Caloric Restriction,” Cell Reports, 22(9), 2395-2407.
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