A Short Summary of Anti-Aging Interventions

by Gokhan. August 6, 2022. Medical Disclaimer

How to select which intervention to bet on? We’ll look for the following evidence to come up with a strategy:

[Longer human lifespan] Drugs/supplements/lifestyle changes that were shown to lower all cause mortality in long-running human RCTs (Randomized Clinical Trials).
[Longer mice lifespan with some supporting evidence from humans] Drugs/supplements/lifestyle changes that extended mice lifespan with promising outcomes in short-term human RCTs (~causation) or retrospective analyses (~association).
[Treat based on biomarkers] Treat high/low values in your labs and biomarkers (e.g. optimize when they aren’t in the ideal range).
[Track your N=1] Don’t blindly follow statistics; make sure the drug/supplement you’re taking works for you specifically (N=1). Watch how you feel, your energy, any side effects, track your labs over time.

The most ideal intervention checks all four boxes. Less ideal interventions check only 1 or 2 boxes. If the intervention you’re following is based on anecdotes, or purely based on cell (mechanistic) studies, or some theory which wasn’t even verified in mice, those tend to be the least reliable.

Interventions that were shown to extend human lifespan in RCTs (#1)

Statin

[RCT] 13% reduction in all cause mortality (ref) – assuming you have dyslipidemia.
[Mice] +4.1% increase in avg. lifespan (ITP, not statistically significant).
[Mice] +9% increase in lifespan when combined with ACE inhibitor (ref).
[Association] Associated with improved cancer outcomes across many cancer types (ref, ref).

ACE inhibitor

[RCT] 10% reduction in all cause mortality (ref) – assuming you have high BP.
[Mice] 2.3% increase in avg. lifespan (ITP, not statistically significant)
[Mice] +9% increase in lifespan when combined with Statin (ref).
[Association] Associated with improved cancer outcomes across many cancer types (ref).

Aspirin

[RCT] 6% reduction in all cause mortality (ref) – data from primary prevention trials.
[Mice] +2.4% increase in avg. lifespan (ITP, effect mostly seen in males, overall not statistically significant)
[Association] Associated with improved cancer outcomes across many cancer types (ref, ref, ref).

Combination therapy (~ Statin + BP Meds + Aspirin)

[RCT] 20% reduction in all cause mortality from aspirin + statin + BP meds (ref).
[RCT] 31% reduction in CV death/MI/stroke/other major cardiac events from aspirin + statin + BP meds (ref).
[RCT] 24% reduction in CV death/MI/stroke from statin + BP meds (ref).

Testosterone Replacement Therapy (TRT)

[RCT] (53%, 61%, 79%) reduction in all cause mortality for the normal weight, overweight, obese males respectively (ref) – assuming you have low testosterone.
[Association] 47%-56% reduction in all cause mortality (ref).

Caveat: Significant variability exists from individual to individual. Working for the population doesn’t mean a specific treatment will work for you. That’s why you need to make treatment decisions based on the principles #3 and #4 above. Always work with a Dr.

Interventions that were shown to extend mice lifespan with supporting evidence from humans (#2)

Rapamycin:

[Mice] +24.5% increase in avg. lifespan (ITP).
[Mice] Extends mice healthspan via delaying aging across all organ systems studied (ref).
[RCT] Anti-aging effect on human skin (ref).
[RCT] Improvement in both diastolic and systolic age-related measures of heart function (E/A ratio, fractional shortening, and ejection fraction) in the rapamycin-treated dogs. (ref)
[RCT] A variant of rapamycin (called everolimus) enhanced participants’ immune response to flu vaccinations by about 20% after six weeks. (ref)

NAC:

[Mice] +23.7% increase in lifespan when combined with Glycine (not ITP).
[Mice] NAC alone improved lifespan with a more pronounced effect in male mice (ref).
[RCT] Glycine + NAC improved: eGFR, Glucose, Insulin, Glucose, HOMA-IR, IL6, TNF-alpha, HS-CRP, exercise capacity, gait speed, 6 min walk, grip strength in older adults (ref).
[RCT] Similar improvements were seen in adults with HIV (ref).
[Mice, RCT] Effects on cancer are controversial with some positive (ref) and negative (ref, ref) mice studies. Evidence from human clinical trials either show no effect (ref) or positive effect (ref, ref).

Exercise

[Mice] +14% increase in avg. lifespan with bigger benefits in male mice (ref).
[Mice] No lifespan extension from spontaneous exercise (ref).
[RCT] No lifespan extension in the largest RCT, but high intensity interval training group had 49% lower all cause mortality (ref, not statistically significant).
[RCT] 24% reduction in the risk of mortality in patients with cancer and in cancer survivors; 48% reduced risk of recurrence (ref).
[Association] Better exercise ability is associated with all sorts of improved health outcomes. But reverse causation is a huge confounder here (“healthy user bias”), so the numerical benefit from those studies cannot be extrapolated to intervention studies.

Keto Diet

[Mice] +13.6% increase in lifespan (ref). It should be noted that the diet wasn’t carnivorous or high protein — it was moderate protein. It ought to be similar to mediterranean keto (ref).
[RCT] 6-24 months duration human RCTs gave excellent results regarding controlling BP, insulin, and metabolic syndrome (ref, ref).
[Association] Associations between eating low carb and health outcomes are contradictory and controversial (ref, ref).

Acarbose

[Mice] +10.5% increase in lifespan with bigger benefits in male mice (ITP).
[Mice] +29% in male lifespan when combined with Rapamycin vs +22% with Rapa alone (ITP, to be published).
[RCT] 50% reduction in Cardiovascular Disease (CVD) in insulin resistant (ref).
[RCT] 48% reduction in all cause mortality in T2D adults (ref).
[RCT] 64% reduction in the risk of myocardial infarction and 35% reduction in any cardiovascular event amongst T2D adults (ref).
[Association] 14% reduced risk of developing any cancer in T2D adults (ref).

Glucosamine

[Mice] +10% increase in lifespan (not ITP).
- Glucosamine is a mild inhibitor of glycolysis, this creates ROS and cellular stress, upregulating the use of mitochondria.
- Mimics low carb diet (via glycolysis inhibition), and probably makes it easier to stick to it.
[Association] 15-39% reduction in all cause mortality — consistent improvement across studies and countries (ref, ref, ref).
[RCT] HS-CRP was 23% lower compared to placebo (ref).

Spermidine

[Mice] +10% increase in lifespan (not ITP).
- Autophagy is required for the anti-aging effect of spermidine – inhibition of autophagy abolishes the longevity-extending effects of spermidine on yeast, worms and flies.
[Association] 26% reduction in all cause mortality from higher dietary-spermidine intake (ref).
[Association] 18% reduction in all cause mortality from higher Natto intake —a spermidine rich food (ref).
[Cell, Mice] Effects on cancer are controversial. Increased intake may accelerate the growth of established tumors (ref) or not (ref).

Grape Seed Extract

[Mice] +9% increase in lifespan (not ITP).
- Shows senotherapeutic activity.
[RCT] Beneficial metabolic effects with lowering blood pressure and improving blood flow (ref, ref).
[Cell, Mice] Anticancer activity against many cancers. (RCT, ref)

Vitamin C

[Mice] +8.6% increase in average lifespan (not ITP).
[RCT] Impressive metabolic effects — lowers elevated HS-CRP (ref), high BP (ref), FBG, HA1C, Insulin, HOMA-IR (ref, ref).

Canagliflozin

[Mice] +14% increase in lifespan in males only (ITP data, paper).
[RCT] 15% lower all cause mortality in T2D adults (ref).
[Cell study, case study] Has impressive effects against kidney cancer (ref).

Icariin (Horny Goat Weed Extract)

[Mice] +8% increase in lifespan (not ITP)
- Activates SIRT6 that is responsible for repairing DNA damage (ref).
- A weak PDE5 inhibitor (ref). Used in formulations that treat erectile function and enhance libido.
[Cell] Inhibited tumor formation in many types of cancer cells (ref).

Green Tea Extract (EGCG)

[Mice] +3.02% increase in lifespan (ITP).
[Mice] +14% increase in lifespan in rats (not ITP).
[Mice] +11% increase in lifespan in mice (not ITP).
[Association] Consuming several cups of green tea daily is associated with 13-15% reduced risk of all-cause mortality (ref, ref)

Cocoa Extract (Epicatechin)

[Mice] +5-8% increase in lifespan (not ITP)
[RCT] 11% reduction in all-cause mortality, 27% reduction in CVD death (ref).
[Association] Chocolate consumption associated with 11-16% all cause mortality reduction (ref).

Glycine

[Mice] +4.57% increase in lifespan (ITP)
[RCT] Increased HGH (ref) and fasting blood sugar (ref) when taken at high doses.

Protandim (~ Bacopa + Milk Thistle + Ashwagandha + Curcumin)

[Mice] +4.31% increase in lifespan (ITP)

AKG

[Mice] +4-5% increase in lifespan (not ITP)
[Association] -7 years of reduced epigenetic age (ref).

Curcumin

[Mice] +1.15% increase in lifespan (ITP, not statistically significant)
[Mice] +10.6% increase in lifespan (not ITP)

Metformin:

[Mice] +2.4% increase in lifespan (ITP, not statistically significant)

[Mice] +5.8% increase in lifespan (not ITP).
[Mice] Works synergistically with Rapamycin (combined, rapa alone).

[Association] Associated with 7% (ref) – 5.2% (ref) reduction in all cause mortality vs non-diabetic controls.
[RCT] Very small survival advantage to metformin, but it isn’t statistically significant (ref).
[Association] Associated with improved cancer outcomes across many cancers (ref).

Fish Oil

[Mice] No effect on mice lifespan (ITP).
[RCT] 7% lower CVD mortality (ref).
[Association] 13% lower all cause mortality (ref).

Resveratrol

[Mice] +2.14% (ITP), +3.64% (ITP) increase in lifespan (not statistically significant)
[Mice] 31% reduced all cause mortality for mice on a high-calorie diet (ref)

Astaxanthin

[Mice] Increased male lifespan statistically significantly (ITP, to be published).

NAD+ Boosters

[RCT] Across studies, no association between Niacin and CVD mortality or all cause mortality (ref, ref)
[RCT] In the longest running study, mortality in the Niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004). (ref)
[Mice] -2.60% decrease in lifespan from NR (ITP, not statistically significant)
[Mice] +5% increase in lifespan from NR (not ITP)
[Mice] No lifespan extension from Nicotinamide (not ITP).
[Cell studies, mice] Controversial. Nicotinamide seems to have broad based beneficial effects against cancer in cell studies and also with non-melanoma skin cancer (ref). Other studies suggested boosting NAD+ can be dangerous in the context of cancer (ref, ref).

Coffee:

[Association] those who drank 4–5 cups of coffee per day had a 12-16% reduced risk of early death in the following 12–13-years. 1 cup per day was associated with a 5–6% lowered risk of early death (ref).
[RCT] With 500ml coffee consumption per day, DNA strand breaks in the coffee group decreased by 23% in comparison with the controls (ref)
[RCT] Supplementation lowered blood pressure (ref).

Fisetin

[Mice] +11% increase in lifespan (not ITP).
[Mice] No lifespan extension (ITP, unpublished)

Other supplements and interventions:

All interventions tested by ITP: ref, ref.
Googling “<XYZ> mice lifespan” usually points you to papers if an intervention has been tested in mice.
Similarly, googling “<XYZ> all cause mortality” usually points you to human RCTs or association studies.

How to build a regimen?

Anti-aging ~ Controlling all of {mTor, blood glucose, lipids, inflammation, oxidation, autophagy, cellular energy, hormones, blood pressure, loss of bodily function…}

Diet & exercise control a majority of these pathways. Beyond those, the following may be considered:

mTor ~ (Rapamycin, Calorie Restriction, Fasting…)

Blood glucose ~ (Low Carb, Acarbose, Metformin, Canagliflozin, …)

Lipids ~ (Statin, Fish Oil, Fiber …)

Inflammation ~ (Statin, Aspirin, Fish Oil, Protandim, Fiber, EGCG, Curcumin, Ginger, Resveratrol…)

Oxidation ~ (NAC, Astaxanthin, EGCG, Cocoa, Coffee, Vit C, …)

Autophagy ~ (Rapamycin, Spermidine, …)

Cellular Energy ~ (AKG, NAD+ Boosters…)

Loss of bodily function ~ (Exercise, Hormones, Glycine, Glucosamine, …)

What to do with this data?

In this article, we’ve considered how to develop an anti-aging regimen based on i) human lifespan experiments (part #1); ii) mice lifespan experiments + short term human RCTs and associations (part #2). If a supplement doesn’t check conditions #1 or #2, perhaps it should be ignored until further studies are conducted.

Even if an intervention checks boxes #1 or #2, it may not agree with you. It’s very important to see how you feel, track your labs regularly & periodically. And, ideally, work with a Dr along the way.

There are some exceptions to following #1 & #2. If an intervention is improving your quality of life while being lifespan-neutral, that’s still a win. Arguably, NAD+ boosters are in this category. They give you more energy, perhaps improve your exercise ability. However, the evidence that NAD+ boosters are lifespan-extending isn’t strong.

Another exception to rules #1 and #2, it’s ok to treat vitamin deficiencies or other abnormal blood markers (through testing — rule #3). Taking vitamins based on test results may be safer than taking a blanket 10x RDA multivitamin — we know that overnutrition is harmful.

Reminder: Nothing on this website is intended as, or should be taken as, medical advice. Medical Disclaimer

References & further reading

This article was heavily influenced by the following people, articles and discussions. The author would like to thank them all. They’re recommended for further reading.

Dr Blagosklonny, “From rapalogs to anti-aging formula”, 2017 (ref).
Vince Guiliano’s blog, videos and list of supplements (ref, ref).
Scientific posts & discussions on Rapamycin Facebook group (ref), Nils Osmar’s Life Extension group (ref).

ITP (ref), Dr Blagosklonny (twitter), Dr Alan Green (web page), Matt Kaeberlein (twitter), Peter Attia (twitter), Rhonda Patrick (twitter) …

An old mice drinking from a man-made fountain of youth

About the Author

Gokhan lives in San Francisco Bay Area. He works as a machine learning engineer and manager in a Silicon Valley company. A researcher in spirit, he’s got his PhD in Electrical and Computer Engineering from Cornell University in 2005. He’s grown a deep interest in life extension and the science of anti-aging. His goal is to extend the healthy human lifespan by bringing more awareness into this area.