The Geroprotectors: 7 Anti-aging Interventions Backed By Science, Part 3


Various geroprotectors are the third leg of a stool that can help you achieve a long healthspan; possibly even a longer lifespan. The first leg is caloric restriction, the second is exercise, and here I review four molecules that comprise the third leg of a multi-prong strategy to live long and strong.


Four geroprotectors round out my three-part series (here’s Part 1 and Part 2) on the seven anti-aging interventions that a slew of scientific studies support as valuable molecules to aid in your effort to extend your healthspan.

Here’s the four:

  1. AKG
  2. Spermidine
  3. Rapamycin
  4. Metformin/Berberine

Two things to know about this list:

  1. It’s is not an exhaustive list; in fact, I’m researching several others that have equivalent benefits that will be part of an anti-aging course I’m working on.
  2. Of the four geroprotectors, only two are available over the counter; the other two require a prescription, and one of them can be dangerous.

Mainly, the reason these molecules are geroprotective, meaning (in this case) a molecule that can affect the root cause of aging and age-related diseases, is that they mimick caloric restriction (discussed in Part 1) and reduce systemic inflammation, or inflammaging.

Lets dive in to find out how…


(1) Alpha-Ketoglutarate (AKG)

AKG is short for “alpha-ketoglutarate”, which is one of two ketone derivatives of glutaric acid. It’s a key molecule in the Krebs cycle, which is basically a big part of how we derive energy from food.

In September 2020, the Buck Institute for Research on Aging published a press release that said, among other things:

Middle-aged mice that had the naturally-occurring metabolite alpha-ketoglutarate (AKG) added to their chow had a better “old age.” They were healthier as they aged and experienced a dramatically shorter time of disease and disability before they died, a first for research involving mammals.

Previous studies show that blood plasma levels of AKG can drop up to 10-fold as we age.

Fasting and exercise, already shown to promote longevity, increase the production of AKG. AKG is not found in the normal diet, making supplementation the only feasible way to restore its levels.

Why are mice considered excellent models for humans?

From The Jackson Laboratory:

Humans and mice don’t look alike, but both species are mammals and are biologically very similar.

Almost all of the genes in mice share functions with the genes in humans. That means we develop in the same way from egg and sperm, and have the same kinds of organs (heart, brain, lungs, kidneys, etc.) as well as similar circulatory, reproductive, digestive, hormonal and nervous systems. These similarities make it possible for scientists to study the physiology of mice to glean information about how human beings grow, develop diseases and age.

This genetic similarity also means that mice and humans inherit traits in the same way. This includes physical traits such as hair color (coat color in mice) and susceptibility to diseases such as heart disease or Alzheimer’s.

Because mice live short lives compared to humans — about two years in laboratory care, but much less in the wild — it’s possible to learn a great deal about how chronic diseases progress over a lifetime, and about the processes of aging. Mice are small and relatively economical to maintain, making them the ideal laboratory animal model.

Thousands of laboratory mouse strains are now available, so scientists can therefore choose the ideal mouse model to study different diseases and disease processes. And the mouse genome is easily manipulated in order to create even more precise models of specific diseases.

Because scientists have been studying laboratory mice for more than 100 years, more is known about their biology and genetics than any animal except for humans. This sheer volume of data, maintained and provided to the worldwide scientific community by The Jackson Laboratory as the Mouse Genome Database, makes the mouse the model of choice for biomedical research.

A 2020 study published in Cell Metabolism found that AKG has longevity effects in the mouse cohort studied, even when first administered at a relatively old age (for mice) at 18 months. The authors underscore that if translated to humans, this effect would be highly desirable, extending lifespan, but more importantly, reducing the debilitating period of functional decline and disease management.
Here’s why:
In vitro data (test tubes) show that AKG can reduce the inflammatory secretions (called “SASP”) from senescent cells (zombie cells, neither dead or alive that become prominent as we age), an important finding given that recent findings have shown that the SASP from senescent cells can drive age-related pathologies  [1] [2], and can activate inflammatory pathways in immune cells [3, 4].
We observed no significant adverse effects of AKG administration. The only phenotypes that had a higher incidence in AKG-treated animals were cataracts and corneal opacity, although neither reached statistical significance. AKG has been used in human clinical studies linked to diseases without associated adverse effects [5, 6, 7].
In humans, plasma AKG levels are reported to decline 10-fold between the ages of 40 and 80 [8], but the molecule is not available in the human diet, making direct supplementation the only feasible route to restore levels.
AKG has a good human safety record, which along with the other our findings showing that it suppresses inflammaging, point to a potential safe human intervention that may impact important elements of aging and improve quality of life in the elderly population.
Which leads me to a May 14, 2021 interview with the former head of the Buck, Prof Brian Kennedy entitled Extending healthspan: AKG, human clinical trials & aging biomarkers. I encourage you to watch the interview below. Note that the AKG part begins at time stamp 06:30, and that Prof Kennedy underscores the biggest potential value of AKG supplementation as an effective geroprotector — extending healthspan, the years over which you’re healthy.


I use Doublewood AKG, 1,000 mg per serving (two capsules).


(2) Spermidine

Spermidine is a naturally occurring polyamine (an organic compound having more than two amino groups) that triggers autophagy, and is associated with lifespan extension when supplemented in the food supply of yeast, flies, and worms [9].

Spermidine concentrations in the body (endogenous) decrease as the organism age, including in humans with the exception of centenarians [10]. Acute injections of spermidine in mice activate autophagy in multiple organs [11], while chronic spermidine feeding promotes increase in healthspan [12].

Given that spermidine increases autophagy, it’s unsurprising that the result is improved healthspan. Dr. Yoshinori Ohsumi won a Nobel Prize for showing how cellular autophagy detoxifies and repairs cells, thereby making them healthier [13].

In addition to upregulating autophagy, spermidine:

  • Can impede a number of neurological pathologies and induce neuronal autophagy (in nerve cells).
  • Can extend lifespan in two short-lived mouse models after oral administration of spermidine 

Spermidine has also been studied in humans:

The foods richest in spermidine are:

  • Soybeans
  • Green peas (I even put them in my oatmeal…. yeah, a fanatic)
  • Potatoes
  • Chicken
  • Pears
  • Mushrooms

Two major spermidine geroprotectors are:


(3) Rapamycin

Rapamycin is a natural product secreted by a soil bacterium originally discovered on Easter Island (also known as Rapa Nui, hence the name rapamycin). Before its introduction in the anti-aging field, rapamycin was already well known as an immunosuppressive drug for the treatment of organ transplants.

Rapamycin is a strong inducer of autophagy, and it extends lifespan in all organisms tested so far, including yeast, flies, worms, and mice [14, 15]. Middle-aged mice on a diet supplemented with rapamycin survive significantly longer than the placebo group [16]; however, reports of the potent immunosuppressive properties of rapamycin suggest that the drug is unsuitable for lifespan extension in humans. Moreover, long-term administration of rapamycin has been found to cause a variety of adverse health effects in patients, including impaired wound healing, anemia, proteinuria (increased levels of protein in the urine), pneumonitis (inflammation of lung tissue), and hypercholesterolemia (high blood cholesterol).

The potential ill effects of rapamycin on humans does not stop some people from using it. Dr Alan Green uses it himself and operates a rapamycin clinic, and longevity expert Dr. Peter Attia has extensively researched and appears to use it tentatively. In the video below, he and Tim Ferriss talk rapa:


For more about rapamycin, read my post, Do These 2 Anti-aging Pills Really Work? Part 1.


(4) Metformin/Berberine

Metformin was first isolated from the French lilac, and over the past 60-some years, has become the most prescribed drug for the treatment of type-2 diabetes. This is because metformin decreases hepatic gluconeogenesis (the biochemical pathway in which glycogen breaks down into glucose-1-phosphate and glycogen) and increases insulin sensitivity [17].

Metformin is a potent, indirect activator of adenosine monophosphate-acti vated protein kinase (AMPK), [18], an enzyme involved in cellular and whole-organism energy balance, as well as in glucose and fat metabolism. AMPK is also induced by caloric restriction and exercise.

Upon metformin exposure, AMPK is activated by an increase of the AMP/ATP ratio, thereby inhibiting mTOR, a protein kinase (an enzyme) involved in the control of cellular proliferation and tumor growth [19]. There’s basically an inverse relationship between mTOR and lifespan, so downregulating it is a good thing.

Metformin increases the mean and maximum lifespan in different female mouse strains predisposed to high incidence of mammary tumors [20] [21]. Many laboratories have tested pharmacological interventions as CR mimetics that can delay aging and the incidence of age-related diseases [22, 23, 24, 25]. The goal here is to find molecules that can make the body think it’s calorically deprived in order to activate certain cellular nutrient-signalling that confer healthspan and longevity benefits.

Some metabolic effects of metformin resemble those of caloric restriction, even though food intake was increased [26, 27]. At a biochemical level, metformin supplementation is associated with inhibition of chronic inflammation and reduction in markers of oxidative stress, two well-known factors that compromise health and lifespan (28).

Unfortunately, you can’t get metformin without a doctor’s prescription, and it seems to reduce the beneficial effects of exercise, so if you were to use it, it’s advisable that it be taken on non-exercise days. (See my post,Can Metformin Side Effects Diminish Physical Fitness?)

Berberine — a chemical found in some plants like European barberry, goldenseal, goldthread, Oregon grape, phellodendron, and tree turmeric — has similar properties to metformin, and is used as a substitute (I’m taking it). But berberine has not been as widely studied as metformin, is poorly absorbed, may be troublesome (see below) for those with high cholesterol, and is probably not as effective relative to improving healthspan or lifespan, although it does well vis a vis metformin to control blood sugar.

Be aware of this about berberine:

  • If you elect to take berberine, take it in low doses and pulse it’s use, one month on, one off.
  • If you’re prediabetic or have type 2 diabetes, consult your doctor about the effectiveness of berberine for you, the proper dose and the schedule for being on and off it.
  • If you have high cholesterol or are on statins,  consult your doctor before taking berberine, An editorial published by the BMJ Journal recommends taking the statin-like red yeast rice extract along with berberine if you have high cholesterol and do not tolerate statins. In addition, the editorial recommends the use of astaxathin for those with high cholesterol. (I use this brand.)

A good berberine brand is made by Toniiq. That said, although it claims it’s highly bioavailablity, other than its high degree of purity, I saw nothing in the ingredients that would make it more absorbable. According to a 2020 study, you can improve the absorption of berberine by taking chitosan with it.

In the video below, Dr. Brad Stanfield reviews the science behind metformin and berberine:


For more about metformin, read my post, Do These 2 Anti-aging Pills Really Work? Part 2.


Other Geroprotector Molecules

Resveratrol*, rapamycin, spermidine and metformin/berberine are four molecules (geroprotectors) that research has shown to be promising brakes on the aging process, but there are a handful of others have excited geroscientists for their potential, and are being actively studies.

Among them are senolytics (fistein, quercetin and piperlongumine), NAD+ precursors (NMN, NR and niacin), hyaluronic acid, TMG, Apigenin and several more.

I will be evaluating all these potential anti-aging molecules in my forthcoming anti-aging course. Get on the list and be notified when it’s ready for enrollment. (You’ll also get the Sunday Newsletter, an Anti-aging Plan on Google Sheets and my four-part guide —  Transform Your Body and Mind.)

*Update (9/20/21): There's some controversy about the benefits of resveratrol. If you currently use resveratrol, or are considering it, make sure you read my update.


Your Takeaway from the Three-part Series

Let’s review the bottom line assertions made by the various studies I referenced in this three-part series about seven anti-aging interventions.

Remember this from Part 1 about caloric restriction (CR) and fasting:

CR can improve a wide array of chronic diseases, such as metabolic syndrome, cognitive disorders and obesity.

A CR scheme that alternatives between under-feeding and regular feeding can approximate the benefits of continuous CR and is easier to maintain. There are several ways to doing CR on an intermittent bassis, such as:

Remember this from Part 2 about exercise:

  • Consistently performing muscle/strength building, mobility and cardiovascular exercise might not make you live longer, but you’ll live longer better.
  • You can predict your mortality by a set of tests that test various performance measures, such as grip strength and walking speed — so test yourself if you need some incentive to start working out.
  • Exercise works to improve your longevity in many ways, beginning at the epigenetic level (exercise can alter gene expression) as well as reducing or reversing the usual muscle wasting (sarcopenia) that occurs as we age.
  • Exercise vastly improves metabolic health, which includes metrics such as body composition, blood sugar, cholesterol, agility and hormone balance (such as increasing testosterone).
  • Exercise can keep your mind intact, as it improves neuroplasticity, and thereby cognitive health.

Remember this from what you just read, Part 3, about four compounds that may help you avoid many of the chronic diseases associated with aging, and thereby extend your healthspan:

  • AKG (alpha-ketoglutarate) can improve healthspan by reducing the damaging inflammatory secretions made by senescent cells, which accumulate in greater number as we age.
  • Spermidine can improve healthspan by upregulating autophagy, our cells’ self-cleaning mechanism that enables them to be healthier.
  • Rampaycin has improved the lifespan of all animal models it was tested on, but can be dangerous for humans, as it can repress our immune system. Some people are experimenting with doses, but it should be avoided until more studies are done that indicate it could be safe at a certain dose and interval.
  • Metformin has a long track record of reducing blood sugar and is currently being tested for potential life extension effects in humans, which have already been shown in other humans. Because a prescription is needed, a good, but potentially less safe substitute is berberine. If you elect to take berberine, take it in low doses and pulse it’s use, one month on, one off.

Collectively, the the three-part series covered these seven anti-aging interventions:

  1. Caloric Restriction
  2. Fasting
  3. Exercise
  4. AKG
  5. Spermidine
  6. Rapamycin
  7. Metformin/Berberine

This may be a lot to get your arms around, so choose whichever is the lowest hanging fruit that you’re willing to reach for. Once you’ve munched on that for awhile, reach up and grab another, and another until you’re all gooey with fruit juice and getting younger every day.



Last Updated on July 7, 2023 by Joe Garma

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Joe Garma

I help people live with more vitality and strength. I'm a big believer in sustainability, and am a bit nutty about optimizing my diet, supplements, hormones and exercise. To get exclusive Updates, tips and be on your way to a stronger, more youthful body, join my weekly Newsletter. You can also find me on LinkedIn, Twitter and Instagram.

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