Life Extension Possibilities

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.)

Intervention Longevity Increase
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%
Selegiline 7%
Metformin 4-5%

Bottom Lines

  • 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.

Low methionine

60 Fischer rats fed a low-methionine diet lived 30% longer than control rats. The low-methionine rats grew significantly less as well.[1]

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.[2]’

Some tumors are dependent on methionine to grow and will not kill methionine-starved mice as fast.[28]

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[32] and schizophrenia.[33]  Homocysteine is toxic and reacts to “homocysteinylate” many different kinds of proteins, rendering them ineffective.[29]  It might also cause its damage through oxidation, impaired methylation, or other chemical mechanisms.[30]  If you give a rabbit homocysteine injections, it’ll develop atherosclerosis.[31]

Children with homocysteinuria have been successfully treated with low-methionine diets.[34][35][36] 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. [3]

Ames dwarf mice lack growth hormone, prolactin, and TSH, and live about 50% longer than normal mice due to a Prop1 mutation.[22]

Humans with Prop1 mutations lack growth hormone and so have short stature, hypothyroid, cortisol deficiency, and failure to go through puberty.[37]  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.[38]

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.[23]  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.[39]

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.

Metformin

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%.[4]

Metformin increases the mean lifespan of mice by 4-5%. Treated mice had lower cholesterol, lower LDL, and lower insulin.[7]

Rapamycin

If fed to mice near the end of lifespan (600 days), rapamycin extends mean lifespan by 14% for females and 9% for males.[5]  Rapamycin fed to mice starting at 9 months extends median survival by 10% in males and 18% in females.[6]  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.[8]

High-dose rapamycin given to mice at 9 months extends life by 23% in males and 26% in females.[9]

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.[15]

NDGA

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.[11]

NDGA increased median lifespan in male mice, but not female mice, by 8-10%.[12]

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.[10]  Mice given tocopherol from 28 weeks and maintained in the cold (45 degrees Fahrenheit) lived 15% longer.[56]  On the other hand, high-dose vitamin E in humans, according to a meta-analysis, did not reduce all-cause mortality.[57]

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.[13]  Lower core body temperature is one of the results of caloric restriction, and cooler humans tend to live longer and be less obese.[55]

Young Ovaries

Old mice transplanted with young mouse ovaries lived an average of 6% longer.[14]  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.[54]

Selegiline

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.[16] However, later studies could never find an equally dramatic effect. Mice treated with selegiline starting at 18 months had no increase in survival.[17] Selegiline extends life in female but not male Syrian hamsters.[18] Fischer rats treated starting at 18 months with selegiline lived 7% longer.[19] Male Fischer rats treated starting at 12 months with selegiline lived 7% longer.[20] Female hamsters, but not male, treated with selegiline, lived significantly longer than controls.[24]

ACE Inhibitors

High dose ACE inhibition with ramipril doubled the lifespan of hypertensive rats, bringing it up to that of normal rats.[21] Statins + ramipril increased lifespan of long-lived mice by 9%.[53]

Ramipril is a standard drug for high blood pressure.

AC5 Knockout

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.[25]  AC5 knockout mice also have markedly attenuated responses to pain (heat, cold, mechanical, inflammation, and neuropathic.)[50]  The effects of morphine and mu or delta opioid receptor agonists are attenuated in AC5 knockout mice.[52] However, AC5 knockout mice had Parkinson’s-like motor symptoms.[51]

SIRT1 Activators

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. [49]

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.[26]  SRT1720 reduces liver lipid accumulation in strains of mice bred for obesity and insulin resistance, and preserved liver function.[45]

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.[46]

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.[47]

The putative SIRT1 activator SRT2104 did not affect insulin or glucose in a randomized trial of type II diabetes.[48]

Investigation of the sirtuin drugs has shut down, due to these failures to replicate.

PAPP-A Knockout

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.)[27]  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.[42]  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.[43]  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.[44] 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.[40]  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.[41]

Dogs

Selegiline

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.[65]

Ovaries

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).[66]

IGF and Weight

IGF is positively correlated with weight, and negatively correlated with age, in dogs across various breeds.  Larger dogs live less long. [67]

Humans

FOXO3A Mutation

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.[58]  A German sample of long-lived people found that minor alleles were 1.53x as common in centenarians than controls.[59]

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.[60]

FOXO3 is activated by AMPK.[61] You can do this via metformin in vitro — meanwhile changing glioma precursor cells into non-tumor cells.[62]  You can also do it with AICAR, an AMP analogue that stimulates AMPK.[63]  Note that AICAR reduces triglycerides, increases HDL, lowers blood pressure, and reverses insulin resistance in mice.[64]

Unsupported Musings

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.

References

[1]Orentreich, Norman, and JAYA ZIMMERMAN. “Low methionine ingestion by rats extends life span.” Age (days) 1050 (1993): 1300.

[2]Miller, Richard A., et al. “Methionine‐deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF‐I and insulin levels, and increases hepatocyte MIF levels and stress resistance.” Aging cell 4.3 (2005): 119-125.

[3]Shimokawa, Isao, et al. “Life span extension by reduction in growth hormone-insulin-like growth factor-1 axis in a transgenic rat model.” The American journal of pathology 160.6 (2002): 2259-2265.

[4]Anisimov, Vladimir N., et al. “If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice.” Aging (Albany NY) 3.2 (2011): 148-157.

[5]Harrison, David E., et al. “Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.” nature 460.7253 (2009): 392-395.

[6]Miller, Richard A., et al. “Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice.” The Journals of Gerontology Series A: Biological Sciences and Medical Sciences (2010): glq178.

[7]Martin-Montalvo, Alejandro, et al. “Metformin improves healthspan and lifespan in mice.” Nature communications 4 (2013).

[8]Anisimov, Vladimir N., et al. “Rapamycin extends maximal lifespan in cancer-prone mice.” The American journal of pathology 176.5 (2010): 2092-2097.

[9]Miller, Richard A., et al. “Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction.” Aging cell 13.3 (2014): 468-477.

[10]Navarro, Ana, et al. “Vitamin E at high doses improves survival, neurological performance, and brain mitochondrial function in aging male mice.” American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 289.5 (2005): R1392-R1399.

[11]Strong, Randy, et al. “Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice.” Aging cell 7.5 (2008): 641-650.

[12]Harrison, David E., et al. “Acarbose, 17‐α‐estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males.” Aging cell 13.2 (2014): 273-282.

[13]Conti, Bruno, et al. “Transgenic mice with a reduced core body temperature have an increased life span.” Science 314.5800 (2006): 825-828.

[14]Mason, Jeffrey B., et al. “Transplantation of young ovaries to old mice increased life span in transplant recipients.” The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 64.12 (2009): 1207-1211.

[15]Livi, Carolina B., et al. “Rapamycin extends life span of Rb1+/-mice by inhibiting neuroendocrine tumors.” Aging (Albany NY) 5.2 (2013): 100-110.

[16]Knoll, Joseph. “The striatal dopamine dependency of life span in male rats. Longevity study with (−) deprenyl.” Mechanisms of ageing and development 46.1 (1988): 237-262.

[17]Ingram, Donald K., et al. “Chronic treatment of aged mice with L-deprenyl produces marked striatal MAO-B inhibition but no beneficial effects on survival, motor performance, or nigral lipofuscin accumulation.” Neurobiology of aging 14.5 (1993): 431-440.

[18]Stoll, S., et al. “Chronic treatment of Syrian hamsters with low-dose selegiline increases life span in females but not males.” Neurobiology of aging 18.2 (1997): 205-211.

[19]Kitani, K., et al. “Chronic treatment of (-) deprenyl prolongs the life span of male Fischer 344 rats. Further evidence.” Life sciences 52.3 (1993): 281-288.

[20]Bickford, P. C., et al. “Long-term treatment of male F344 rats with deprenyl: assessment of effects on longevity, behavior, and brain function.” Neurobiology of aging 18.3 (1997): 309-318.

[21]Linz, Wolfgang, et al. “Long-term ACE inhibition doubles lifespan of hypertensive rats.” Circulation 96.9 (1997): 3164-3172.

[22]Bartke, Andrzej, et al. “Longevity: extending the lifespan of long-lived mice.” Nature 414.6862 (2001): 412-412.

[23]Selman, Colin, et al. “Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice.” The FASEB Journal 22.3 (2008): 807-818.

[24]Stoll, S., et al. “Chronic treatment of Syrian hamsters with low-dose selegiline increases life span in females but not males.” Neurobiology of aging 18.2 (1997): 205-211.

[25]Yan, Lin, et al. “Type 5 adenylyl cyclase disruption increases longevity and protects against stress.” Cell 130.2 (2007): 247-258.

[26]Mitchell, Sarah J., et al. “The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet.” Cell reports 6.5 (2014): 836-843.

[27]Conover, Cheryl A., and Laurie K. Bale. “Loss of pregnancy‐associated plasma protein A extends lifespan in mice.” Aging cell 6.5 (2007): 727-729.

[28]Hoffman, Robert M. “Methioninase: a therapeutic for diseases related to altered methionine metabolism and transmethylation: cancer, heart disease, obesity, aging, and Parkinson’s disease.” Human cell 10 (1997): 69-80.

[29]Krumdieck, Carlos L., and Charles W. Prince. “Mechanisms of homocysteine toxicity on connective tissues: implications for the morbidity of aging.” The Journal of nutrition 130.2 (2000): 365S-368S.

[30]Perna, Alessandra F., et al. “Possible mechanisms of homocysteine toxicity.” Kidney International 63 (2003): S137-S140.

[31]McCully, Kilmer S., and Bruce D. Ragsdale. “Production of arteriosclerosis by homocysteinemia.” The American journal of pathology 61.1 (1970): 1.

[32]Tolmunen, Tommi, et al. “Association between depressive symptoms and serum concentrations of homocysteine in men: a population study.” The American journal of clinical nutrition 80.6 (2004): 1574-1578.

[33]Applebaum, Julia, et al. “Homocysteine levels in newly admitted schizophrenic patients.” Journal of psychiatric research 38.4 (2004): 413-416.

[34]Perry, ThomasL, et al. “Treatment of homocystinuria with a low-methionine diet, supplemental cystine, and a methyl donor.” The Lancet 292.7566 (1968): 474-478.

[35]Kolb, Felix O., Jerry M. Earll, and Harold A. Harper. ““Disappearance” of cystinuria in a patient treated with prolonged low methionine diet.” Metabolism 16.4 (1967): 378-381.

[36]Sardharwalla, I. B., et al. “Homocystinuria: a study with low-methionine diet in three patients.” Canadian Medical Association Journal 99.15 (1968): 731.

[37]Reynaud, Rachel, et al. “A familial form of congenital hypopituitarism due to a PROP1 mutation in a large kindred: phenotypic and in vitro functional studies.” The Journal of Clinical Endocrinology & Metabolism 89.11 (2004): 5779-5786.

[38]Guevara-Aguirre, Jaime, et al. “Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans.” Science translational medicine 3.70 (2011): 70ra13-70ra13.

[39]Suh, Yousin, et al. “Functionally significant insulin-like growth factor I receptor mutations in centenarians.” Proceedings of the National Academy of Sciences 105.9 (2008): 3438-3442.

[40]Lawrence, James B., et al. “The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A.” Proceedings of the National Academy of Sciences 96.6 (1999): 3149-3153.

[41]Bayes-Genis, Antoni, et al. “Pregnancy-associated plasma protein A as a marker of acute coronary syndromes.” New England Journal of Medicine 345.14 (2001): 1022-1029.

[42]Conover, Cheryl A., et al. “Metabolic consequences of pregnancy-associated plasma protein-A deficiency in mice: exploring possible relationship to the longevity phenotype.” Journal of Endocrinology 198.3 (2008): 599-605.

[43]Vallejo, Abbe N., et al. “Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A.” Proceedings of the National Academy of Sciences 106.27 (2009): 11252-11257.

[44]Conover, Cheryl A., et al. “Preferential impact of pregnancy-associated plasma protein-A deficiency on visceral fat in mice on high-fat diet.” American Journal of Physiology-Endocrinology and Metabolism 305.9 (2013): E1145-E1153.

[45]Yamazaki, Yu, et al. “Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice.” American Journal of Physiology-Endocrinology and Metabolism 297.5 (2009): E1179-E1186.

[46]Libri, Vincenzo, et al. “A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers.” PLoS One 7.12 (2012): e51395.

[47]Pacholec, Michelle, et al. “SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.” Journal of Biological Chemistry 285.11 (2010): 8340-8351.

[48]Baksi, Arun, et al. “A phase II, randomized, placebo‐controlled, double‐blind, multi‐dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes.” British journal of clinical pharmacology 78.1 (2014): 69-77.

[49]Cantó, Carles, and Johan Auwerx. “Caloric restriction, SIRT1 and longevity.” Trends in Endocrinology & Metabolism 20.7 (2009): 325-331.

[50]Kim, K‐S., et al. “Markedly attenuated acute and chronic pain responses in mice lacking adenylyl cyclase‐5.” Genes, Brain and Behavior 6.2 (2007): 120-127.

[51]Iwamoto, Tamio, et al. “Motor dysfunction in type 5 adenylyl cyclase-null mice.” Journal of Biological Chemistry 278.19 (2003): 16936-16940.

[52]Kim, Kyoung-Shim, et al. “Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action.” Proceedings of the National Academy of Sciences of the United States of America 103.10 (2006): 3908-3913.

[53]Spindler, Stephen R., Patricia L. Mote, and James M. Flegal. “Combined statin and angiotensin-converting enzyme (ACE) inhibitor treatment increases the lifespan of long-lived F1 male mice.” AGE 38.5-6 (2016): 379-391.

[54]Cargill, Shelley L., et al. “Age of ovary determines remaining life expectancy in old ovariectomized mice.” Aging cell 2.3 (2003): 185-190.

[55]Waalen, Jill, and Joel N. Buxbaum. “Is older colder or colder older? The association of age with body temperature in 18,630 individuals.” The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 66.5 (2011): 487-492.

[56]Banks, Ruth, John R. Speakman, and Colin Selman. “Vitamin E supplementation and mammalian lifespan.” Molecular nutrition & food research 54.5 (2010): 719-725.

[57]Miller, Edgar R., et al. “Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality.” Annals of internal medicine 142.1 (2005): 37-46.

[58]Willcox, Bradley J., et al. “FOXO3A genotype is strongly associated with human longevity.” Proceedings of the National Academy of Sciences 105.37 (2008): 13987-13992.

[59]Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (Feb 2009). “Association of FOXO3A variation with human longevity confirmed in German centenarians”. Proceedings of the National Academy of Sciences of the United States of America. 106 (8): 2700–5.

[60]Morris, Brian J., et al. “FOXO3: a major gene for human longevity-a mini-review.” Gerontology 61.6 (2015): 515-525.

[61]Greer, Eric L., et al. “The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor.” Journal of Biological Chemistry 282.41 (2007): 30107-30119.

[62]Sato, Atsushi, et al. “Glioma‐Initiating Cell Elimination by Metformin Activation of FOXO3 via AMPK.” Stem cells translational medicine 1.11 (2012): 811-824.

[63]Li, Xiao-Nan, et al. “Activation of the AMPK-FOXO3 pathway reduces fatty acid–induced increase in intracellular reactive oxygen species by upregulating thioredoxin.” Diabetes 58.10 (2009): 2246-2257.

[64]Buhl, Esben S., et al. “Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome.” Diabetes 51.7 (2002): 2199-2206.

[65]Ruehl, W. W., et al. “Treatment with L-deprenyl prolongs life in elderly dogs.” Life sciences 61.11 (1997): 1037-1044.

[66]Waters, David J., et al. “Exploring mechanisms of sex differences in longevity: lifetime ovary exposure and exceptional longevity in dogs.” Aging Cell 8.6 (2009): 752-755.

[67]Greer, Kimberly A., Larry M. Hughes, and Michal M. Masternak. “Connecting serum IGF-1, body size, and age in the domestic dog.” Age 33.3 (2011): 475-483.

[68]Arteaga, Silvia, Adolfo Andrade-Cetto, and René Cárdenas. “Larrea tridentata (Creosote bush), an abundant plant of Mexican and US-American deserts and its metabolite nordihydroguaiaretic acid.” Journal of ethnopharmacology 98.3 (2005): 231-239.

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12 thoughts on “Life Extension Possibilities

  1. Thanks for this!

    I’ve been wondering for a while, and I having found much information: are there any tradeoffs I can make between health and longevity? That is, is there anything that can slow cognitive decline, protect against arthritis, keep skin looking young, strengthen bones etc etc but that raises my odds of dying young?

    I see testosterone being marketed as doing this for men, but it also looks like it could severe nonfatal brain damage via a stroke, so it might not be what I’m looking for. Is there, like, a googleable term for this tradeoff and research related to it?

    • I think growth hormone and testosterone are good for short-term muscle growth and fat loss but increase risk of diseases of aging. Caloric restriction seems to be the opposite: makes you less fertile and worsens physical performance in the short-run, but might make you live longer.

  2. You point to vegan diets as low in methionine, but the protein staples of a vegan diet — beans, nuts, soy, and seeds — appear to have similar levels of methionine as meat and cheese. (According to nutritional information at https://www.healthaliciousness.com/articles/high-methionine-foods.php, which in turn references USDA National Nutrient Database for Standard Reference, Release 27.)

    If this is the case, a low methionine diet is not preferentially vegan, and instead is just low protein.

    • yeah, it’s not quite the same, I was going from a 1960’s description of a low-methionine diet which consisted mostly of vegetables, butter, and a special soy protein mixture formulated to avoid methionine.

  3. “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.”

    This surprised me. I had been under the impression that the idea that a vegan diet is good for you was very popular among people who also had non-health-related reasons for promoting veganism, but unpopular among people who didn’t, which makes the hypothesis sound pretty suspicious. I have no idea what your views on the externalities of consuming animal products are, but that lit review definitely does not pattern-match to the result of a halo effect around veganism.

  4. For what its worth there are a whole bunch of studies (observational and longitudinal rather than controlled) on seventh day Adventists finding lower risk of mortality for people who eat less meat. I don’t think those were sponsored by veggie advocates, most were done by cancer researchers iirc.

    • I totally buy that CR works; I didn’t discuss it here to save myself time, because the literature on CR is enormous and pretty consistently positive.

  5. There is some evidence that vegan diets actually increase homocysteine levels:
    “Elevated homocysteine concentration in plasma was observed in 66% of the vegans and about 45-50% of the omnivores and vegetarians. Vegan subjects had significantly higher mean plasma homocysteine levels than omnivores.”
    In the same paper, they conclude that this is due to vitamin B_2 and B_12 deficiencies.
    “Thiamin and folate need not be a problem in a well-planned vegan diet. Vitamins B(12) and B(2) may need attention in the strict vegan diet, especially regarding elevated homocysteine levels in plasma.”
    https://www.ncbi.nlm.nih.gov/pubmed/16988496

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