Epistemic Status: Pretty confident
This is my first pass of a lit review of life-extension interventions apart from caloric restriction, with a focus on things that work in mammals (rather than fruit flies or other invertebrates.)
|Ames dwarf mice||50%|
|PAPP-A knockout mice||38%|
|Irs knockout mice||32% (female only)|
|AC5 knockout mice||32%|
|Low methionine diet||30%|
|High dose rapamycin||25%|
|High dose vitamin E||15% females, 40% males|
|Lower core body temperature||12% males, 20% females|
|Low dose rapamycin||10-18%|
|NGDA||10% (male only)|
|Statins + ACE inhibitors||9%|
- Low methionine diets (roughly, vegan diets) work really well at extending life in mice, and there’s a plausible mechanism (avoiding homocysteine buildup) that they might work in humans as well. If it worked as well on humans as it does on mice, the average person would live to over 100.
- Rapamycin extends life in mice by quite a lot. Unfortunately it’s a strong immunosuppressant, so isn’t very safe to use as a drug.
- There’s a lot of evidence that the IGF/insulin signaling/growth hormone metabolic pathway is associated with aging and short lifespan, and that inhibiting genes on that pathway results in longer lifespan. IGF-receptor-inhibiting or growth-hormone-inhibiting drugs could be studied for longevity, but haven’t yet.
- The MAO inhibitor selegiline extends life in both mice and dogs.
- Metformin seems to work, and is currently being studied in a human trial.
- NDGA, an antioxidant derived from the creosote bush, might work, but it’s also toxic.
- Sirtuin drugs and resveratrol don’t work.
60 Fischer rats fed a low-methionine diet lived 30% longer than control rats. The low-methionine rats grew significantly less as well.
80 female mice fed a low-methionine diet lived longer than control mice, at p < 0.02; they also were lower in weight, lower in IGF, insulin, glucose, and thyroxine, had fewer cataracts, and experienced less loss of liver function in response to injected acetaminophen.’
Some tumors are dependent on methionine to grow and will not kill methionine-starved mice as fast.
Homocysteine is biosynthesized from methionine. Homocysteine levels rise as we age and are associated with many diseases of aging, such as heart disease, cancer, stroke, Alzheimer’s, and presbyopia. Genetic conditions that cause homocysteinuria in younger people cause similar problems: vascular thrombosis, intellectual disability, lens disclocation. Homocysteine levels are also associated with depression and schizophrenia. Homocysteine is toxic and reacts to “homocysteinylate” many different kinds of proteins, rendering them ineffective. It might also cause its damage through oxidation, impaired methylation, or other chemical mechanisms. If you give a rabbit homocysteine injections, it’ll develop atherosclerosis.
Children with homocysteinuria have been successfully treated with low-methionine diets. This is now the standard treatment for patients with genetic homocysteinuria who don’t respond to vitamin B supplementation. A low-methionine diet in humans consists of abstaining from meat, fish, and dairy, instead getting protein from soy and vegetables, and making up the caloric deficit with fat.
Growth Hormone and IGF Inhibition
Rats which were heterozygous for an antisense growth-hormone transgene lived 7-10% longer than control rats. They were also smaller and had lower levels of IGF. 
Ames dwarf mice lack growth hormone, prolactin, and TSH, and live about 50% longer than normal mice due to a Prop1 mutation.
Humans with Prop1 mutations lack growth hormone and so have short stature, hypothyroid, cortisol deficiency, and failure to go through puberty. Humans with growth hormone receptor deficiency in Ecuador had short stature and were obese but had a much lower incidence of cancer and diabetes, and greater insulin sensitivity, than their normal relatives. They did not have higher longevity because they had higher rates of alcoholism and accidents.
Female mice missing an IGF receptor (Irs1 -/-) live 32% longer on average; male Irs1 -/- mice have no change in longevity. These mice are insulin resistant but have reduced fat mass despite eating more. A cohort of Ashkenazi Jewish centenarians had female offspring with 35% higher IGF1 and 2.5 centimeters shorter than age- and sex-matched controls. The centenarians had many mutations in the IGF1 receptor gene. The centenarians with mutations had higher IGF1 and a trend towards shorter height than those without.
Pegvisomant is a growth hormone receptor antagonist used to treat acromegaly; it could be investigated as an anti-aging therapy. Somatostatin analogs such as octreotide and pasireotide could also be investigated; somatostatin inhibits the release of growth hormone. There are also IGF receptor kinase inhibitors being investigated for antitumor properties, such as NVP-AEW-541.
If started at 3 months of age (but not later), metformin increased mean lifespan of female SHR mice by 14%. It also delayed the onset of the first tumor by 22%.
Metformin increases the mean lifespan of mice by 4-5%. Treated mice had lower cholesterol, lower LDL, and lower insulin.
If fed to mice near the end of lifespan (600 days), rapamycin extends mean lifespan by 14% for females and 9% for males. Rapamycin fed to mice starting at 9 months extends median survival by 10% in males and 18% in females. Rapamycin fed to Her/neu homozygous (cancer-prone) mice caused 4% extension in mean lifespan and 12.4% increase in maximum lifespan. Rapamycin-treated mice were 25% less likely to develop tumors.
High-dose rapamycin given to mice at 9 months extends life by 23% in males and 26% in females.
Rapamycin increases the lifespan of Rb1+/- mice ( a model of neuroendocrine tumors) by inhibiting the incidence of neuroendocrine tumors. Mean lifespan increased by 9% in females and 14% in males. Treated mice were significantly less likely to have thyroid tumors, and had smaller tumors of all kinds.
Nordihydroguaiaretic acid, an antioxidant derived from the creosote bush, increased mean lifespan by 12% in male but not female mice. Did not increase the proportion of extremely long-lived mice.
NDGA increased median lifespan in male mice, but not female mice, by 8-10%.
On the other hand, there have been reports of hepatitis and kidney damage from human consumption of NDGA or creosote.
High-dose Vitamin E
Male mice given tocopherol (an antioxidant) at a dose of 5g/kg of food from 28 weeks of age had 40% longer median lifespan than control, and 17% increased maximal lifespan; female mice given tocopherol had 15% increased median lifespan. Mice given tocopherol from 28 weeks and maintained in the cold (45 degrees Fahrenheit) lived 15% longer. On the other hand, high-dose vitamin E in humans, according to a meta-analysis, did not reduce all-cause mortality.
Lower Core Body Temperature
Mice genetically engineered to overexpress the Hrct-UCP2 gene, which causes an 0.3-0.5 degree drop in core body temperature, had median lifespans increased by 12% in males and 20% in females. Lower core body temperature is one of the results of caloric restriction, and cooler humans tend to live longer and be less obese.
Old mice transplanted with young mouse ovaries lived an average of 6% longer. In particular, mice ovariectomized before puberty and transplanted with ovaries at 11 months lived longer than intact mice, by 17%. Transplantation with ovaries at 11 months seems to shift the survival curve to the right, postponing aging.
Male rats treated with deprenyl (aka selegiline, a Parkinson’s drug and MAO-B inhibitor) lived on average 35% longer than controls, according to a 1988 study. However, later studies could never find an equally dramatic effect. Mice treated with selegiline starting at 18 months had no increase in survival. Selegiline extends life in female but not male Syrian hamsters. Fischer rats treated starting at 18 months with selegiline lived 7% longer. Male Fischer rats treated starting at 12 months with selegiline lived 7% longer. Female hamsters, but not male, treated with selegiline, lived significantly longer than controls.
High dose ACE inhibition with ramipril doubled the lifespan of hypertensive rats, bringing it up to that of normal rats. Statins + ramipril increased lifespan of long-lived mice by 9%.
Ramipril is a standard drug for high blood pressure.
Adenylyl cyclase 5 is primarily expressed in the heart and brain, and catalyzes the synthesis of cyclic AMP, an important second messenger which allows hormones to pass through the plasma membrane and activates protein kinases, in particular to regulate glucose and fat metabolism.
AC5 knockout mice have a median lifespan 32% longer than wild-type mice. Bones were less brittle, body weights were smaller, and GH levels were lower. AC5 knockout mice also have markedly attenuated responses to pain (heat, cold, mechanical, inflammation, and neuropathic.) The effects of morphine and mu or delta opioid receptor agonists are attenuated in AC5 knockout mice. However, AC5 knockout mice had Parkinson’s-like motor symptoms.
Sirtuin 1, determined by the SIRT1 gene, is downregulated in cells that have high insulin resistance, and increased in mice undergoing caloric restriction; mice with low levels of SIRT1 don’t live longer in response to caloric restriction, while mice with high levels mimic the caloric restriction phenotype. 
SRT1720, a SIRT1 activator, extends life by 8% in mice on a standard diet, and by 21.7% in mice fed a high-fat diet (who are generally shorter-lived). SRT1720 also reduces the incidence of cataracts, improves glucose tolerance, and lowers LDL and cholesterol. SRT1720 reduces liver lipid accumulation in strains of mice bred for obesity and insulin resistance, and preserved liver function.
A phase I trial of SRT1720 in elderly human volunteers found that it was safe and well-tolerated and reduced cholesterol, LDL, and triglycerides over the course of a month of treatment.
However, a subsequent trial found that SRT1720 does not in fact activate SIRT except when SIRT is attached to a fluorophore (used for imaging), so it may be an artifact. This study also found that SRT1720 had no effect on glucose tolerance in mouse models of diabetes.
The putative SIRT1 activator SRT2104 did not affect insulin or glucose in a randomized trial of type II diabetes.
Investigation of the sirtuin drugs has shut down, due to these failures to replicate.
Mice missing pregnancy-associated plasma protein A live 38% longer than control mice, not associated with changes in serum glucose, cholesterol, or dietary intake. Wild-type mice had many more tumors than knockout mice. (70% of wild-type vs. 15% of knockout had tumors.) Knockout mice are smaller than wild-type, and consume less food, though similar as a proportion of bodyweight; they also show more spontaneous physical activity. Knockout mice are not significantly different from wild-type in terms of insulin sensitivity, fasting glucose, or insulin levels. PAPP-A knockout mice do not demonstrate as much thymic atrophy in old age as wild-type mice: more immature thymus cells, more new T cells, less IGF1 expression, easier to activate T cells. IGF-1 promotes differentiation of T cells, so releasing it slower could keep the thymus young longer. PAPP-A knockout and wild-type mice both gain similar amounts of subcutaneous fat on high-fat diets, but the knockout mice gain significantly less visceral fat; PAPP-A is most highly expressed in mesenteric fat. PAPP-A may have some tissue-specific effects on promoting IGF-axis activity, without altering metabolism that much across the board.
PAPP-A encodes a metalloproteinase that cleaves insulin-like growth factor binding proteins. These IGFBPs are inhibitors of IGF activity, and if you cleave them, the ability to inhibit IGF diminishes; so PAPP-A knockouts make IGF less bioavailable. PAPP-A is expressed in unstable atherosclerotic plaques but not in stable ones; serum PAPP-A levels are higher in patients with unstable angina or acute myocardial infarction than in patients with stable angina or controls, by about a factor of two.
80% of dogs receiving selegiline, compared to 39% of elderly (age 10-15) dogs receiving placebo, survived to the end of the two-year study.
Female dogs who had their ovaries removed lived no longer than male dogs, while dogs with ovaries were twice as likely as male dogs to achieve “exceptional” longevity (>13 years).
IGF and Weight
IGF is positively correlated with weight, and negatively correlated with age, in dogs across various breeds. Larger dogs live less long. 
Homozygous minor mutations in the FOXO3A gene were associated with a 2.75 odds ratio of being in a cohort of long-lived men, compared to controls. They were 29% more likely to be “healthy” at baseline (free of cardiovascular disease, cancer, stroke, Parkinson’s, and diabetes, able to pass a walking and a cognitive test). The mutations were 85% more common in people who lived to more than 100 than in people who died at 72-74. A German sample of long-lived people found that minor alleles were 1.53x as common in centenarians than controls.
Insulin-like growth factor signaling inhibits FOXO3 activity, while oxidative stress activates FOXO3. FOXO3 represses the mTOR pathway and promotes DNA repair. It is also anti-inflammatory: suppresses IL-2 and IL-6, reduces proliferation of T cells and lymphocytes, reduces inflammation.
FOXO3 is activated by AMPK. You can do this via metformin in vitro — meanwhile changing glioma precursor cells into non-tumor cells. You can also do it with AICAR, an AMP analogue that stimulates AMPK. Note that AICAR reduces triglycerides, increases HDL, lowers blood pressure, and reverses insulin resistance in mice.
I don’t think antioxidants generally have come out looking too good for anti-aging, and there are a lot of counterexamples to the “aging is oxidative damage” hypothesis.
I think the growth-hormone-and-insulin-signaling cluster of life extension techniques and mutations is probably a real thing, and matches well to an explanation for why caloric restriction works. It also makes sense evolutionarily; in times of food abundance you want to reproduce, while in times of food scarcity you just want to survive the season, so it would make sense if you had two hormonal modes, “reproductive mode” and “survival mode.”
I also think there’s probably an mTOR mechanism, possibly just due to cancer, that explains the effectiveness of both rapamycin and the significance of the FOXO3 genes. AMPK, which is produced by exercise, is upstream of both the mTOR stuff and the insulin-signaling stuff; this would explain why both exercise and metformin seem to be helpful for longevity.
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