Possible Interventions to Test

By Sarah Constantin

These are some summary notes on twelve interventions that seem potentially worth testing in mammals. 

Epitalon

 

What it is

A tetrapeptide (Ala-Glu-Asp-Gly) synthesized to match the most common amino acids in the pineal gland extract epithalamin.

 

Patent Status

Patented 2004 by Vladimir Khavinson[1].

 

Evidence for Effectiveness

  • Increases max (but not mean) lifespan in SHR mice by 12.3%.[2]
  • Increases max lifespan in CBA mice by 42%, mean by 5%.[3]
  • Increases melatonin production, increases daytime cortisol, and decreases nighttime cortisol in aged monkeys, making their hormones more like young monkeys’.[4]
  • Reduces spontaneous mammary tumors in HER-2/neu female mice.[5]
  • Reduces spontaneous mammary tumors in C3H/He female mice.[6]

 

Hypothesized Mechanism

Regularizing circadian rhythm.

 

Proposed study

Lifespan, motor & cognitive tests, autopsy



C3 Carboxyfullerene

 

What it is

A buckyball with three carboxyl groups.

 

Patent Status

Application abandoned by Laura Dugan et al in 2002.[7]

 

Evidence for Effectiveness

  • Increases lifespan in C57BL6 mice by 11%, improves age-related decline in cognitive function.[8]
  • Improves Parkinson’s symptoms in MPTP-lesioned monkeys.[9]
  • Prevents iron-induced neurological injury in rats.[10]
  • Prevents injury-induced cerebral ischemia in mice.[11]
  • Delays death in a mouse model of ALS.[12]

 

Hypothesized Mechanism

Antioxidant, neuroprotective. SOD mimetic.

 

Proposed study

Dose-response, motor & cognitive tests, autopsy, inflammation markers.

 

Key Researcher

Laura Dugan, Vanderbilt University

 

Selegiline

 

What it is

A substituted phenethylamine and MAOI.

 

Patent Status

Available as a generic drug.  FDA approved for Parkinson’s disease and depression.

 

Evidence for Effectiveness

  • 31% lifespan increase in rats.[13]
  • 50% lifespan increase in immunosuppressed mice[14].
  • 6-9% lifespan increase in heterozygous aged mice.[15]
  • 16% lifespan increase in aged rats.[16]
  • Increases lifespan in elderly dogs.[17]
  • Reduces ischemic brain damage in rats.[18]
  • Reestablishes estrous cycles and prevents mammary and pituitary tumors in old rats.[19]
  • Protects against MPTP-induced neurotoxicity in primates.[20]

 

Hypothesized Mechanism

Neuroprotective.

 

Proposed study

Lifespan in C57BL6 or UM-HET3 mice; motor, cognitive, autopsy.

 

Key Researchers

Laszlo Koles, Semmelweis University

 

Nicotinamide Mononucleotide

 

What it Is

NAD+ precursor; form of vitamin B3.

 

Patent Status

May be patented. (E.g. https://patents.justia.com/patent/9919003)

 

Evidence for Effectiveness

  • Improves activity levels, insulin sensitivity, reduces body weight gain, improves eye function, in aged mice.[21]
  • Restores insulin sensitivity in mouse age-induced type II diabetes.[22]
  • Protects the mouse heart from ischemia/reperfusion injury.[23]
  • Reverses age-related vascular dysfunction in mice.[24]

 

Hypothesized Mechanism

NAD+ & SIRT1.

 

Proposed Study

Lifespan study; motor, cognitive, autopsy; metabolic or inflammation biomarkers.

 

Epithalamin

 

What it is

A peptide extract from calf pineal glands.

 

Patent Status

Not patented.

 

Evidence for Effectiveness

  • Preserves estrus, delays tumor onset, and increases lifespan by 25% when given to female rats.[25][26]
  • Preserves estrus, reduces tumor burden, and extends median lifespan 6.5% when given to aged rats.[27]
  • Increases nighttime melatonin production in healthy elderly subjects.[28]
  • Reduces 12-year all-cause mortality in elderly subjects with cardiovascular disease by 28%.[29]
  • Reduces 6-year all-cause mortality in healthy elderly subjects by 49%[30]

 

Hypothesized Mechanism

Circadian rhythm.

 

Proposed Study

Lifespan in C57BL6 or UM-HET3 mice; motor, cognitive, autopsy; melatonin & cortisol levels; day/night activity patterns.

 

Melatonin

 

What it is

Hormone produced by the pineal gland.

 

Patent Status

Many patents, but perhaps not aging-specific; sold as a supplement.

 

Evidence for Effectiveness

Increases mean lifespan by 5.4% in female CBA mice.[31]

Increases max lifespan by 15% in female SHR mice; also preserves estrus and reduces tumor burden.[32]

Increases lifespan of male, but not female C3H mice by 20%.[33]

Increases median lifespan of female BALB/c mice by 23.5% and in male C57BL/6 mice by 17.3%.[34]

 

Hypothesized Mechanism

Circadian rhythm.

 

Proposed Study

Lifespan, motor, cognitive, biopsy on UM-HET3 mice.  Day/night activity patterns.

 

Key Researchers

Gregory Oxenkrug, Tufts University

 

Spermidine

 

What it Is

A polyamine molecule found in ribosomes.

 

Patent Status

Many patents, but perhaps not aging-specific.

 

Evidence for Effectiveness

Increases lifespan in C57BL/6 mice by 10%, improves cardiac function, increases autophagy.[35]

Polyamine-rich chow extends lifespan in Jc1:ICR mice by 29% and reduces glomerulosclerosis.[36]

Prevents retinal degeneration in a mouse model of optic nerve injury.[37]

Extends life by 25% and rescues liver failure in autophagy-deficient mice.[38]

Reverses age-related arterial stiffness and endothelial dysfunction in C57BL/6 mice.[39]

 

Proposed Study

Lifespan, motor, cognitive, autopsy on UM-HET3 mice.

 

Hypothesized Mechanism

Autophagy.

 

Key Researchers

Frank Madeo, University of Graz, Austria

 

Stem Cell Transplants

 

What it Is

Mesenchymal stem cells from young animals injected intravenously after radiation treatment to kill host stem cells.

 

Patent Status

Many patents, but perhaps not aging-specific.

 

Evidence for Effectiveness

  • Increases mean lifespan in Balb/c mice by 16.3%, and increases bone mineral density.[40]
  • Increases progenitor cells in mouse myocardium and improves cardiac recovery from infarction.[41]
  • Increases mean lifespan by 34% in C57Bl/6 mice when transplants are repeated every three months[42].
  • Increases mean lifespan by 6% after a single transplant into C57Bl/6 mice.[43]
  • Improves physical performance battery in elderly healthy patients.[44]

 

Hypothesized Mechanism

Reversing stem cell exhaustion.

 

Proposed Study

Lifespan, motor, cognitive, autopsy on C57Bl/6 or UM-HET3 mice.  Proliferative capacity of bone marrow in transplanted animals compared to control.

 

Researchers to Fund

Liping Tang, UT Arlington

 

N-Acetylcysteine

 

What it Is

Small molecule antioxidant; glutathione precursor.

 

Patent Status

Many patents, but perhaps not aging-specific; available as a supplement

 

Evidence for Effectiveness

  • Increases lifespan by 24% in male but not female UM-HET3 mice. [45]
  • Prevents age-related memory impairment in mice.[46]
  • Improves cognitive performance in a mouse model of Alzheimer’s.[47]

 

Hypothesized Mechanism

Antioxidant.  Possible dietary restriction effect.

 

Proposed study

Lifespan, cognitive, motor, biopsy on UM-HET3 mice in thermoneutral conditions (to correct for possible dietary restriction effect.)

 

Acarbose

 

What it Is

Anti-diabetic drug that inhibits starch digestion.

 

Patent Status

Generic; approved for diabetes.

 

Evidence for Effectiveness

Increases male median lifespan by 22% and female median lifespan by 5% in UM-HET3 mice.[48]

Reduces body weight and improves insulin sensitivity in both mice and humans.[49]

Alleviates age-related memory and learning deficits in a mouse model of Alzheimer’s.[50]

 

Hypothesized Mechanism

Calorie restriction mimetic.

 

Proposed study

Lifespan, cognitive, motor, biopsy on UM-HET3 mice in thermoneutral conditions (to correct for possible dietary restriction effect.)

 

Phenformin

 

What it Is

Biguanide diabetes drug.

 

Patent Status

Pulled from US markets due to risk of fatal lactic acidosis.

 

Evidence for Effectiveness

Increases lifespan in female C3H/Sn mice by 23% and decreases spontaneous tumor incidence.[51]



Hypothesized Mechanism

Calorie restriction mimetic.

 

Proposed study

Lifespan, cognitive, motor, biopsy on UM-HET3 mice in thermoneutral conditions (to correct for possible dietary restriction effect.)

 

Ethoxyquin

 

What it Is

Small molecule antioxidant.

 

Patent Status

Many patents, perhaps not aging-specific.

 

Evidence for Effectiveness

  • Increases lifespan by 18% in C3H mice, and reduces weight.[52]
  • Neuroprotective against cisplatin toxicity.[53]

 

Hypothesized Mechanism

Antioxidant; calorie restriction mimetic.

 

Proposed Study

Lifespan, cognitive, motor, biopsy on UM-HET3 mice in thermoneutral conditions (to correct for possible dietary restriction effect.)

References

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[4]Khavinson, Vladimir, Nadezhda Goncharova, and Boris Lapin. "Synthetic tetrapeptide epitalon restores disturbed neuroendocrine regulation in senescent monkeys." Neuroendocrinology Letters 22.4 (2001): 251-254.

[5]Anisimov, Vladimir N., et al. "Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER‐2/neu transgenic mice." International journal of cancer 101.1 (2002): 7-10.

[6]KOSSOY, GEORGE, et al. "Effect of the synthetic pineal peptide epitalon on spontaneous carcinogenesis in female C3H/He mice." in vivo 20.2 (2006): 253-257.

[7]https://patents.google.com/patent/US20030162837

[8]Quick, Kevin L., et al. "A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice." Neurobiology of aging 29.1 (2008): 117-128.

[9]Dugan, Laura L., et al. "Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates." Annals of neurology 76.3 (2014): 393-402.

[10]Lin, Anya MY, et al. "The Antioxidative Effect of Carboxyfullerenes (C3/D3) on Iron‐Induced Oxidative Injury in CNS." Annals of the New York Academy of Sciences 890.1 (1999): 340-351.

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[12]Dugan, Laura L., et al. "Carboxyfullerenes as neuroprotective agents." Proceedings of the National Academy of Sciences94.17 (1997): 9434-9439.

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[21]Mills, Kathryn F., et al. "Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice." Cell metabolism 24.6 (2016): 795-806.

[22]Yoshino, Jun, et al. "Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet-and age-induced diabetes in mice." Cell metabolism 14.4 (2011): 528-536.

[23]Yamamoto, Takanobu, et al. "Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion." PloS one 9.6 (2014): e98972.

[24]Picciotto, Natalie E., et al. "Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice." Aging Cell 15.3 (2016): 522-530.

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[26]Dilman, V. M., et al. "Increase in lifespan of rats following polypeptide pineal extract treatment." Experimentelle Pathologie 17.9 (1979): 539-545.

[27]Anisimov, V. N., L. A. Bondarenko, and V. Kh Khavinson. "Effect of pineal peptide preparation (epithalamin) on life span and pineal and serum melatonin level in old rats." Annals of the New York Academy of Sciences 673.1 (1992): 53-57.

[28]Korkushko, O. V., et al. "Effect of peptide preparation Epithalamin on circadian rhythm of epiphyseal melatonin-producing function in elderly people." Bulletin of experimental biology and medicine 137.4 (2004): 389-391.

[29]Korkushko, O. V., et al. "Geroprotective effect of epithalamine (pineal gland peptide preparation) in elderly subjects with accelerated aging." Bulletin of experimental biology and medicine 142.3 (2006): 356-359.

[30]Khavinson, Vladimir Kh, and Vyacheslav G. Morozov. "Peptides of pineal gland and thymus prolong human life." Neuroendocrinology Letters 24.3-4 (2003): 233-240.

[31]Anisimov, Vladimir N., et al. "Melatonin increases both life span and tumor incidence in female CBA mice." The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56.7 (2001): B311-B323.

[32]Anisimov, Vladimir N., et al. "Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice." Experimental gerontology 38.4 (2003): 449-461.

[33]Oxenkrug, G., P. Requintina, and S. Bachurin. "Antioxidant and Antiaging Activity of N‐Acetylserotonin and Melatonin in the in Vivo Models." Annals of the New York Academy of Sciences 939.1 (2001): 190-199.

[34]Pierpaoli, Walter, and William Regelson. "Pineal control of aging: effect of melatonin and pineal grafting on aging mice." Proceedings of the National Academy of Sciences 91.2 (1994): 787-791.

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[36]Soda, K., et al. "Polyamine-rich food decreases age-associated pathology and mortality in aged mice." Experimental gerontology 44.11 (2009): 727-732.

[37]Noro, T., et al. "Spermidine promotes retinal ganglion cell survival and optic nerve regeneration in adult mice following optic nerve injury." Cell death & disease 6.4 (2015): e1720.

[38]Yue, Fei, et al. "Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S-mediated autophagy." Cancer research 77.11 (2017): 2938-2951.

[39]LaRocca, Thomas J., et al. "The autophagy enhancer spermidine reverses arterial aging." Mechanisms of ageing and development 134.7-8 (2013): 314-320.

[40]Shen, Jinhui, et al. "Transplantation of mesenchymal stem cells from young donors delays aging in mice." Scientific reports 1 (2011): 67.

[41]Li, Shu-Hong, et al. "Reconstitution of aged bone marrow with young cells repopulates cardiac-resident bone marrow-derived progenitor cells and prevents cardiac dysfunction after a myocardial infarction." European heart journal 34.15 (2012): 1157-1167.

[42]Karnaukhov, Alexey V., et al. "Informational theory of aging: the life extension method based on the bone marrow transplantation." Journal of Biophysics 2015 (2015).

[43]Kovina, Marina, et al. "Effect on lifespan of high yield non-myeloablating transplantation of bone marrow from young to old mice." Frontiers in genetics 4 (2013): 144.

[44]Tompkins, Bryon A., et al. "Allogeneic mesenchymal stem cells ameliorate aging frailty: A phase II randomized, double-blind, placebo-controlled clinical trial." The Journals of Gerontology: Series A 72.11 (2017): 1513-1522.

[45]Flurkey, Kevin, Clinton M. Astle, and David E. Harrison. "Life extension by diet restriction and N-acetyl-L-cysteine in genetically heterogeneous mice." Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 65.12 (2010): 1275-1284.

[46]Martı́nez, Marcos, Ana Isabel Hernández, and Natividad Martı́nez. "N-Acetylcysteine delays age-associated memory impairment in mice: role in synaptic mitochondria." Brain research 855.1 (2000): 100-106.

[47]Farr, Susan A., et al. "The antioxidants α‐lipoic acid and N‐acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice." Journal of neurochemistry 84.5 (2003): 1173-1183.

[48]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.

[49]Brewer, Rachel A., Victoria K. Gibbs, and Daniel L. Smith Jr. "Targeting glucose metabolism for healthy aging." Nutrition and healthy aging 4.1 (2016): 31-46.

[50]Tong, Jing-Jing, et al. "Chronic acarbose treatment alleviates age-related behavioral and biochemical changes in SAMP8 mice." Behavioural brain research 284 (2015): 138-152.

[51]Dilman, Vladimir M., and Vladimir N. Anisimov. "Effect of treatment with phenformin, diphenylhydantoin or L-dopa on life span and tumour incidence in C3H/Sn mice." Gerontology26.5 (1980): 241-246.

[52]Comfort, A., I. Youhotsky-Gore, and K. Pathmanathan. "Effect of ethoxyquin on the longevity of C3H mice." Nature 229.5282 (1971): 254.

[53]Zhu, Jing, et al. "Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity." Scientific reports 6 (2016): 28861.