A Short Summary of Antiaging Interventions
A SHORT SUMMARY OF LONGEVITY INTERVENTIONS
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) — the gold standard in research. Additionally, we will consider interventions that are associated with increased human longevity, though the evidence from RCTs might be still emerging.
[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 least reliable.
Interventions that were shown to extend human lifespan in RCTs (#1)
Weight loss
[Association] Optimal BMI that minimizes the risk of all cause mortality is between 20-24 (ref).
[RCT] Lifestyle interventions: 15% reduction in all cause mortality after 5.5 kg avg. weight loss (ref).
[Association] Bariatric surgery: 38%-41% reduction in all cause mortality (ref, ref) after 10%-27% avg. weight loss (ref, ref, ref).
[RCT] Anti-diabetic drugs: Tirzepatide 22.5% (ref), Semaglutide 17% (ref), Acarbose 3%-7.5% (ref, ref, ref), Metformin 5.6% (ref) weight loss.
Once you become obese, permanent weight loss through diet and exercise is very unlikely (2019). Metformin, Acarbose, SLT2-i are very helpful for small weight loss. For big permanent weight loss, GLP1-RA class of drugs and surgery are very effective.
LDL Lowering Meds / Statin
[RCT, Association] Optimal LDL-C appears to be as low as possible, ideally maintained at low levels starting from an as early age as possible. Aggressively lowering LDL-C < 70 mg/dL can stop progression of atherosclerotic plaques and may even cause some plaque regression (ref, ref, ref).
[RCT] 8%-13% reduction in all cause mortality in primary prevention (ref, ref) – assuming you have dyslipidemia.
[Mice] +4.1% increase in avg. lifespan (ITP, not statistically significant). +9% increase in lifespan when a statin is combined with ACE inhibitor (ref).
[Association] Associated with improved cancer outcomes across many cancer types (ref, ref).
BP Meds / ACE inhibitor
[RCT] Intensive BP lowering therapy (SBP <120 mm Hg) resulted in +2.9 years additional lifespan compared to the standard BP lowering (SBP <140 mm Hg). The intensive arm demonstrated improved brain health (ref, ref).
[RCT] 10% reduction in all cause mortality from using ACE inhibitors (ref) – assuming you have high BP.
[Mice] +5% increase in avg. lifespan from Captopril (ITP). +2.3% increase in avg. lifespan from Enalapril (ITP, not statistically significant). +9% increase in lifespan when combined with Statin (ref).
[Association] Associated with improved cancer outcomes across many cancer types (ref).
Combination therapy (~ Statin + BP Meds + Aspirin)
[RCT] 20% reduction in all cause mortality from aspirin + statin + BP meds (ref).
[RCT] 34% reduction in major adverse cardiovascular events (MACE) 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).
Flu vaccine (ref)
[RCT] 11%-42% reduction in all cause mortality in RCTs and prospective cohort studies (ref, ref, ref).
[Association] 43% reduction in all cause mortality, which was a very consistent finding across 40+ studies (ref, ref).
[Association] All cause mortality was reduced in adults with diabetes (ref), hypertension (ref), cardiovascular disease (ref), cancer (ref).
[Association] Lowered Alzheimer's risk by 25-40% (ref, ref).
Multivitamin
[RCT] Trend towards 6% reduction in all-cause mortality across primary prevention trials (RR: 0.94; 95% CI: 0.89, 1.00) (ref).
[RCT] Taking a basic RDA level multivitamin (Centrum Silver) for 3 years slowed cognitive decline in healthy older adults by 60% (ref).
[RCT] 8% reduction in cancer risk from a basic RDA level multivitamin (ref).
Vitamin D3
[RCT] Trend towards 5% reduction in all cause mortality HR=0.95 (0.91 to 1.00, p=0.07). 15% reduced risk of cancer mortality HR=0.85 (0.74 to 0.97). (ref)
Fish Oil (EPA)
[RCT] Trend towards 3% reduced all-cause mortality (RR = 0.97, 95% CI = 0.94–1.01). 7%-8% reduced risk of CVD mortality (RR = 0.92, 95% CI = 0.87–0.98). More significant mortality reduction with higher dose and EPA-rich omega-3. (ref, ref)
[RCT] 20% reduction in HS-CRP (ref), significantly reduced depression (ref, ref).
[Mice] No effect on mice lifespan (ITP).
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.
Honor roll: Interventions that are associated with longer human lifespan
Exercise
[Association] 40% lower all cause mortality from a combination of aerobic and anaerobic exercise (ref). But reverse causation is a huge confounder here (“healthy user bias”), so the numerical benefit from those studies cannot be extrapolated to intervention studies.
[RCT] Exercise did not reduce all-cause mortality and incident CVD in older adults or in people with chronic conditions, based on RCTs comprising ∼50,000 participants (ref).
[RCT] 24% reduction in the risk of mortality in patients with cancer and in cancer survivors; 48% reduced risk of recurrence (ref).
[Mice] +14% increase in avg. lifespan with bigger benefits in male mice (ref). No lifespan extension from spontaneous exercise (ref).
Mediterranean style diets (ref)
[Association] 20%-56% reduction in all cause mortality by following a mediterranean style diet (ref, ref).
[RCT] Trend towards 12% reduction in all cause mortality. 30% reduced risk of MI, Stroke or CVD death (ref).
[RCT] 50%-70% reduction in the risk of recurrent heart disease (ref).
Will to Live and Enjoy Life
[Association] A strong will to live and enjoyment of life are associated with reduced all-cause mortality (ref, ref, ref)
Consider supplements, drugs and lifestyle factors that increase mental faculties, motivation, pleasure from daily activities.
B Vitamins (B Complex, Vit B1, Glylo, NAD+ precursors etc)
Exercise, Coffee, EPA, Selegiline, Mood enhancers…
Being socially active.
Green tea & its extract (EGCG)
[Association] Consuming several cups of green tea daily is associated with 13-20% reduced risk of all-cause mortality (ref, ref, ref, ref)
[Mice] +3.02% increase in lifespan in genetically heterogenous mice (ITP), +14% increase in lifespan in rats (not ITP), +11% increase in lifespan in mice (not ITP).
Cocoa & its extract (Epicatechin)
[Association] Chocolate consumption is associated with 11-16% all cause mortality reduction (ref).
[RCT] 11% reduction in all-cause mortality, 27% reduction in CVD death (ref).
[Mice] +5-8% increase in lifespan (not ITP)
Natto
[Association] 18% reduction in all cause mortality from higher Natto intake —a spermidine, vit K2 and nattokinase rich food (ref).
[RCT] High dose nattokinase may reverse the progression of Coronary Artery Calcification (ref).
Fiber
[Association] 15%-30% reduced risk of death and chronic diseases in people who included the most fiber in their diets, compared with those with the lowest intake (ref).
Garlic
[Association] 8%-11% reduced risk of death by consuming garlic occasionally or often (ref).
[RCT] Slows down the progression of Coronary Artery Calcification (CAC) (ref, ref). Helps lower BP (ref). Beneficial effects on lipid profile (ref), inflammation (ref), fatty liver, thrombosis risk (ref).
[Mice] Extended the lifespan of senescence accelerated mouse and C elegans. (ref, ref, ref).
Glucosamine
[Association] 15-39% reduction in all cause mortality — consistent improvement across studies and countries (ref, ref, ref).
[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.
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).
Aspirin
[RCT] While earlier studies showed 5%-6% reduction in all cause mortality in primary prevention (ref), the more recent data is decidedly neutral (ref, ref) — 10% reduction in major CVD events (MACE) with a similar increase in major bleeding events (ref), essentially canceling out the benefits.
[Association] Associated with improved cancer outcomes across many cancer types (ref, ref, ref).
[Mice] +2.4% increase in avg. lifespan (ITP, effect mostly seen in males, overall not statistically significant)
Emerging therapies: Interventions that were shown to extend mice lifespan with some supporting evidence from humans (#2)
Calorie Restriction (CR) / One Meal A Day (OMAD)
[Mice] +33% increase in avg. lifespan from eating OMAD & 30% CR (not ITP).
[RCT] Clinical trial of 14% CR in normal weight humans gave excellent results over a 2yr time horizon. CR was shown to be a legitimate life extension tool through improved biomarkers (ref).
[RCT] The only clinical trial of OMAD showed a significant reduction in fat mass (ref). Unfortunately, this study collected the subjects’ vitals and blood samples at different times of day. Because these values (especially blood pressure and cortisol) are subject to variation during the day, this is a significant source of confounding (ref).
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, 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).
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).
PPARγ activators (Pioglitazone)
[Mice] 11% increase in median lifespan by PPARγ activation (ref).
[Association] 33%-55% reduction in all cause mortality in T2D adults (ref, ref, ref).
[RCT] improves insulin sensitivity and targets many features of aging (ref). Consistently lowers HS-CRP (ref). Reduces visceral fat, specifically in the liver (ref, ref).
Taurine
[Mice] +11% increase in lifespan (ref).
Human studies haven’t shown broad based benefits with this supplement yet.
Acarbose
[Mice] +10.5% increase in lifespan with bigger benefits in male mice (ITP).
[Mice] +32.5% increase in lifespan when combined with Rapamycin vs +24.5% with Rapa alone (ITP).
[RCT] 50% reduction in Cardiovascular Disease (CVD) in adult prediabetics (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).
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).
Creatine
[Mice] +9% increase in lifespan (ref).
[Cell, Mice] Mixed effects on cancer. Supplementation may accelerate the invasion and metastasis of colorectal cancer, breast cancer and pancreatic cancer amongst other cancer promoting effects (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] +0%-14% increase in lifespan in female/male mice, respectively (ITP data, paper).
[RCT] 15% lower all cause mortality in T2D adults (ref).
[Cell study, case study] Has impressive effects against kidney cancer (ref) and other cancers.
Glylo (~ Thiamine + Nicotinamide + Vitamin B6 + Lipoic acid)
[Mice] 8.2% increase in median lifespan (not ITP)
Ameliorates age-associated decline by inducing voluntary calorie restriction, reducing glycation and improving insulin sensitivity.
Works when started late in life (24 months old mice ~ 60-70 yrs old human-equivalent).
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).
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
Curcumin
[Mice] +1.15% increase in lifespan (ITP, not statistically significant). +10.6% increase in lifespan (not ITP)
Metformin:
[Mice] +2.4%-+5.8% increase in lifespan (ITP not statistically significant, not ITP). Works synergistically with Rapamycin (combined, rapa alone).
[Association] 20%-28% reduction in all cause mortality in T2D adults (ref, ref).
[RCT] Very small survival advantage to metformin, but it isn’t statistically significant (ref).
[Association] Associated with improved cancer outcomes across many cancers (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
[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).
[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)
[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).
Fisetin
[Mice] +11% increase in lifespan (not ITP).
[Mice] No lifespan extension (ITP, unpublished)
Other supplements and interventions
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, Pioglitazone, …)
Lipids ~ (Statin, Fish Oil, Fiber …)
Inflammation ~ (Statin, Pioglitazone, Aspirin, Fish Oil, Protandim, Fiber, EGCG, Curcumin, Ginger, Resveratrol…)
Oxidation ~ (NAC, Astaxanthin, EGCG, Cocoa, Coffee, Vit C, …)
Autophagy ~ (Rapamycin, Spermidine, …)
Cellular Energy ~ (AKG, Glylo, 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 antiaging 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.
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
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