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A list of interventions that are likely to be among the first officially recognized treatments for human lifespan extension

Image credit: Christina Victoria Craft / Unsplash

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Jamila
Jamila Nov 18, 2020
Aging affects each and every one of us. So, researchers have been testing out whether lifespans can be improved by using certain interventions. Significant lifespan improvements have been reported in animal models like C. elegans, mice models, etc. However, the same is yet to be described in humans.

Which interventions are likely to be the first officially recognized treatments for human lifespan extension? And why do you think that?

[1]Neff, Frauke, et al. "Rapamycin extends murine lifespan but has limited effects on aging." The Journal of clinical investigation 123.8 (2013): 3272-3291.

[2]De Haes, Wouter, et al. "Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2." Proceedings of the National Academy of Sciences 111.24 (2014): E2501-E2509.

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Hyperbaric Oxygen Therapy (HBOT)

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Shubhankar Kulkarni
Shubhankar Kulkarni Nov 24, 2020
Scientists from Tel Aviv and the Shamir medical center successfully conducted a 3-month HBOT trial on 30 senior participants. The HBOT was breathing 100% oxygen by mask at 2 absolute atmospheres for 90 minutes. The therapy was administrated in a Multiplace Starmed-2700 chamber. It was administered daily (a total of 60 sessions across 3 months). Each session included 5-minute air breaks every 20 minutes.

There was a significant decrease in the number of senescent Helper-T and Cytotoxic-T cells after the HBOT. The levels of HIF-1alpha (Hypoxia-inducible factor 1-alpha) increased significantly but dropped within 2 weeks of the end of the therapy suggesting that the therapy is not a one-time solution but needs to be continued life-long. There was also a significant increase in the relative telomere length of the B-cells and Helper-T and Cytotoxic-T cells due to the therapy.

The current study looked at the molecular characteristics of the cells in the blood. Whether HBOT has a similar effect (increase in the relative telomere length of the cells and a decrease in the number of senescent cells) on the cells in other organs needs to be addressed.

[1]Hachmo Y, Hadanny A, Abu Hamed R, Daniel-Kotovsky M, Catalogna M, Fishlev G, Lang E, Polak N, Doenyas K, Friedman M, Zemel Y, Bechor Y, Efrati S. Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells : a prospective trial. Aging (Albany NY). 2020; . https://doi.org/10.18632/aging.202188 [Epub ahead of print]

Rapamycin

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Shubhankar Kulkarni
Shubhankar Kulkarni Nov 20, 2020
Advantages:
  1. The TOR (nutrient sensing) pathway is activated by nutrients, insulin, and growth factors. TOR increases protein synthesis, inhibits autophagy, and may develop compensatory resistance to insulin, growth hormone, and growth factors. TOR drives geroconverison (from quiescence to senescence), which lasted 3-6 days in cell culture and takes decades in the human body. mTOR makes the cells hypertrophic and leads to SASP, which then causes age-related pathologies. There is no natural bodily inhibitor of TOR. Rapamycin inhibits TOR.
  2. Rapamycin is a natural anti-fungal produced by soil bacteria Streptomyces hygroscopicus.
  3. Rapamycin extends longevity (3-fold) in short-lived strain of mice, and prolongs life in normal mice, yeast, flies, and worms, and prevents age-related conditions, even in humans.
  4. Rapamycin is FDA-approved and is used as anti-aging drugs since 2006.
  5. Rapamycin improves immunity in cancer patients and the elderly, reduces CMV (Cytomegalovirus) infection in transplant patients. Rapamycin is indicated in almost all age-related disease like cancer, obesity, neurodegeneration, and atherosclerosis . No study has shown that Rapamycin causes cancer.
  6. Rapamycin in an effective anti-aging drug irrespective of age. It would be most effective if it is used early, before the disease manifests.
  7. Intermittent Rapamycin and calorie restriction (24-48 hours after) when combined, avoids hyperglycemia. Rapamycin both prevents and abrogates insulin resistance even in humans.
  8. Physical exercise, if started immediately after Rapamycin use, can take advantage of Rapamycin-induced lipolysis as fuel for the muscles. Chronic Rapamycin treatment does not reduce muscle endurance and prevents muscle loss.
  9. A daily 1 mg/day for several weeks in the elderly did not have side-effects.
Disadvantages:
  1. Rapamycin may interact with other drugs and that may lead to hyperglycemia.
  2. Rapamycin is required to activate or rejuvenate the stem cells. However, it needs to be withdrawn for the rejuvenated stem cells to induce regeneration and healing (Rapamycin impairs healing).
  3. At high doses in the elderly, Rapamycin may cause reversible thrombocytopenia, anemia, and leukopenia. However, a slight reduction in platelets is beneficial.
  4. Rapamycin may cause stomatitis and mycositis (ulceration and inflammation of the mucous membranes of the alimentary canal and the digestive tract), non-infectious interstitial pneumonitis, and it may increase the severity of bacterial infections (by inhibiting neutrophil function).

[1]Demidenko ZN, Blagosklonny M V. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle [Internet]. 2008 Nov 5;7(21):3355–61. Available from: http://www.tandfonline.com/doi/abs/10.4161/cc.7.21.6919

[2]Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, et al. mTOR Is Essential for Growth and Proliferation in Early Mouse Embryos and Embryonic Stem Cells. Mol Cell Biol [Internet]. 2004 Aug 1;24(15):6710–8. Available from: https://mcb.asm.org/content/24/15/6710

[3]Blagosklonny M V. Rapamycin for longevity: opinion article. Aging (Albany NY) [Internet]. 2019 Oct 4;11(19):8048–67. Available from: http://www.aging-us.com/article/102355/text

[4]Johnson SC, Yanos ME, Kayser E-B, Quintana A, Sangesland M, Castanza A, et al. mTOR Inhibition Alleviates Mitochondrial Disease in a Mouse Model of Leigh Syndrome. Science (80- ) [Internet]. 2013 Dec 20;342(6165):1524–8. Available from: https://www.sciencemag.org/lookup/doi/10.1126/science.1244360

[5]Blagosklonny M V. Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. Cell Cycle [Internet]. 2006 Sep 15;5(18):2087–102. Available from: https://www.tandfonline.com/doi/full/10.4161/cc.5.18.3288

[6]Svatek RS, Ji N, de Leon E, Mukherjee NZ, Kabra A, Hurez V, et al. Rapamycin Prevents Surgery-Induced Immune Dysfunction in Patients with Bladder Cancer. Cancer Immunol Res [Internet]. 2018 Dec 18; Available from: http://cancerimmunolres.aacrjournals.org/lookup/doi/10.1158/2326-6066.CIR-18-0336

[7]Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med [Internet]. 2014 Dec 24;6(268):268ra179-268ra179. Available from: https://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.3009892

[8]Pascual J, Royuela A, Fernández AM, Herrero I, Delgado JF, Solé A, et al. Role of mTOR inhibitors for the control of viral infection in solid organ transplant recipients. Transpl Infect Dis [Internet]. 2016 Dec;18(6):819–31. Available from: http://doi.wiley.com/10.1111/tid.12601

[9]Carosi JM, Sargeant TJ. Rapamycin and Alzheimer disease: a double-edged sword? Autophagy [Internet]. 2019 Aug 3;15(8):1460–2. Available from: https://www.tandfonline.com/doi/full/10.1080/15548627.2019.1615823

[10]Whyte LS, Lau AA, Hemsley KM, Hopwood JJ, Sargeant TJ. Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer’s disease? J Neurochem [Internet]. 2017 Mar;140(5):703–17. Available from: http://doi.wiley.com/10.1111/jnc.13935

[11]Makki K, Taront S, Molendi-Coste O, Bouchaert E, Neve B, Eury E, et al. Beneficial Metabolic Effects of Rapamycin Are Associated with Enhanced Regulatory Cells in Diet-Induced Obese Mice. Chavakis T, editor. PLoS One [Internet]. 2014 Apr 7;9(4):e92684. Available from: https://dx.plos.org/10.1371/journal.pone.0092684

[12]Zhou W, Ye S. Rapamycin improves insulin resistance and hepatic steatosis in type 2 diabetes rats through activation of autophagy. Cell Biol Int [Internet]. 2018 Sep;42(10):1282–91. Available from: http://doi.wiley.com/10.1002/cbin.11015

[13]Ye L, Widlund AL, Sims CA, Lamming DW, Guan Y, Davis JG, et al. Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance. Aging (Albany NY) [Internet]. 2013 Jul 16;5(7):539–50. Available from: http://www.aging-us.com/article/100576

[14]Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, et al. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol [Internet]. 2018 May;105:53–69. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0531556517309130

[15]Pavlakis M, Goldfarb-Rumyantzev AS. Diabetes after Transplantation and Sirolimus: What’s the Connection? J Am Soc Nephrol [Internet]. 2008 Jul;19(7):1255–6. Available from: http://www.jasn.org/lookup/doi/10.1681/ASN.2008050474

[16]Blagosklonny M V. Aging, Stem Cells, and Mammalian Target of Rapamycin: A Prospect of Pharmacologic Rejuvenation of Aging Stem Cells. Rejuvenation Res [Internet]. 2008 Aug;11(4):801–8. Available from: https://www.liebertpub.com/doi/10.1089/rej.2008.0722

[17]Weiner SM, Sellin L, Vonend O, Schenker P, Buchner NJ, Flecken M, et al. Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome a single-centre experience and review of the literature. Nephrol Dial Transplant [Internet]. 2007 Aug 25;22(12):3631–7. Available from: https://academic.oup.com/ndt/article-lookup/doi/10.1093/ndt/gfm420

[18]Dunn JLM, Kartchner LB, Gast K, Sessions M, Hunter RA, Thurlow L, et al. Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury. J Leukoc Biol [Internet]. 2018 May;103(5):909–18. Available from: http://doi.wiley.com/10.1002/JLB.3AB0616-251RRR

Resveratrol

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Jamila
Jamila Nov 26, 2020
Resveratrol is a compound commonly found in grape skins, peanuts, and other food. Apparently, this compound mediates anti-ageing effects by acting on the AMPK and NAD+ pathways (SIRT1). NAD levels fall as we age.

Advantages
  • Resveratrol supplementation was shown to increase lifespan and improve the healthspan of various models.
  • Resveratrol inhibits oxidative stress, inflammatory response, and much more.
  • Improved cognitive function in postmenopausal women that took 75 mg trans-resveratrol two times a day for a year.
Disadvantages
  • Resveratrol hasn't got a good bioavailability.
  • Genetic factors may impact the effectiveness of the treatment.
I wonder if an improved version of resveratrol has been developed yet.

[1]Bhullar, Khushwant S., and Basil P. Hubbard. "Lifespan and healthspan extension by resveratrol." Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1852.6 (2015): 1209-1218.

[2]Schultz, Michael B., and David A. Sinclair. "Why NAD+ declines during aging: it’s destroyed." Cell metabolism 23.6 (2016): 965-966.

[3]McCormack, Shana, et al. "Pharmacologic targeting of sirtuin and PPAR signaling improves longevity and mitochondrial physiology in respiratory chain complex I mutant Caenorhabditis elegans." Mitochondrion 22 (2015): 45-59.

[4]Jimenez-Gomez, Yolanda, et al. "Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet." Cell metabolism 18.4 (2013): 533-545.

[5]Valenzano, Dario R., et al. "Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate." Current biology 16.3 (2006): 296-300.

[6]Rascón, Brenda, et al. "The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction." Aging (Albany NY) 4.7 (2012): 499.

[7]Gonzalez-Freire, Marta, et al. "The road ahead for health and lifespan interventions." Ageing Research Reviews (2020): 101037.

[8]Zaw, Jay Jay Thaung, Peter RC Howe, and Rachel HX Wong. "Sustained Cerebrovascular and Cognitive Benefits of Resveratrol in Postmenopausal Women." Nutrients 12.3 (2020): 828.

[9]Walle, Thomas, et al. "High absorption but very low bioavailability of oral resveratrol in humans." Drug metabolism and disposition 32.12 (2004): 1377-1382.

[10]Chang, Thomas KH, Jie Chen, and Wendy BK Lee. "Differential Inhibition and Inactivation of Human CYP1 Enzymes bytrans-Resveratrol: Evidence for Mechanism-Based Inactivation of CYP1A2." Journal of Pharmacology and Experimental Therapeutics 299.3 (2001): 874-882.

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Shubhankar Kulkarni
Shubhankar Kulkarnia year ago
In vitro studies have shown that the glycosylated analogs of resveratrol show more powerful bioactivities. For example, resveratrol and piceid have a similar antioxidant capacity, but piceid appears to be more efficacious than resveratrol. [1] Piceid showed a higher scavenging activity against hydroxyl radicals than resveratrol in vitro. [2] Piceatannol is shown to have stronger anti-inflammatory, immunomodulatory, anti-proliferative, anti-leishmanial, anti-leukemic, and protein-tyrosine kinase inhibitory effects. [3]

References:
1. Fabris S, Momo F, Ravagnan G, Stevanato R. Antioxidant properties of resveratrol and piceid on lipid peroxidation in micelles and monolamellar liposomes. Biophys Chem. 2008 Jun;135(1-3):76-83. doi: 10.1016/j.bpc.2008.03.005. Epub 2008 Mar 29. PMID: 18420333.
2. Su D, Cheng Y, Liu M, et al. Comparision of piceid and resveratrol in antioxidation and antiproliferation activities in vitro. PLoS One. 2013;8(1):e54505. doi:10.1371/journal.pone.0054505
3. Fan P, Marston A, Hay AE, Hostettmann K. Rapid separation of three glucosylated resveratrol analogues from the invasive plant Polygonum cuspidatum by high-speed countercurrent chromatography. J Sep Sci. 2009 Sep;32(17):2979-84. doi: 10.1002/jssc.200900057. PMID: 19639547.
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Jamila
Jamila a year ago
Shubhankar Kulkarnithanks for the comment, exciting work!
Piceid seems to have better absorption than resveratrol. In a study, comparisons were made between resveratrol and piceid. Researchers found that the blood concentration of piceid was always 3x more than resveratrol when given the same dosages. [1]

Furthermore, resveratrol and piceid both have neuroprotective abilities. Piceid and resveratrol were able to prevent polymerisation of beta-amyloid. [2] So, they could be used to prevent age-related neurodegeneration.

I would be interested to see comparisons between resveratrol and the derivatives in terms of life extension. 😊

References
1. Wang, Hui-Lin, et al. "Comparative studies of polydatin and resveratrol on mutual transformation and antioxidative effect in vivo." Phytomedicine 22.5 (2015): 553-559.
2. Rivière, Céline, et al. "Inhibitory activity of stilbenes on Alzheimer's β-amyloid fibrils in vitro." Bioorganic & medicinal chemistry 15.2 (2007): 1160-1167.

Calorie restriction

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Deru Xu
Deru Xu Dec 02, 2020
In animal models, calorie restriction has been proven to be one of the most effective interventions to combat these age-related diseases.The researchers compared the difference between rats with a 30% reduction in calorie intake and rats on a normal diet. These rats are between 18 months and 27 months old, roughly equivalent to the age of 50 to 70 years in humans.Even in old age, many tissues and cells in rats with reduced calorie intake are very similar to those of young rats.It shows that proper calorie input can delay aging and even reverse a series of physiological indicators related to aging.Calorie restriction can systematically suppress the increase in inflammatory response (a stress response of the immune system to injury and infection, which usually helps repair the damage and protect the body.) during aging.

[1][1]Ma Shuai,Sun Shuhui,Geng Lingling,Song Moshi,Wang Wei,Ye Yanxia,Ji Qianzhao,Zou Zhiran,Wang Si,He Xiaojuan,Li Wei,Esteban Concepcion Rodriguez,Long Xiao,Guo Guoji,Chan Piu,Zhou Qi,Belmonte Juan Carlos Izpisua,Zhang Weiqi,Liu Guang-Hui. Caloric Restriction Reprograms the Single-Cell Transcriptional Landscape of Rattus Norvegicus Aging[J]. Cell,2020, 180(5).DOI:https://doi.org/10.1016/j.cell.2020.02.008

Integrated stress response inhibitor drug reverses age-related cognitive decline

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Shubhankar Kulkarni
Shubhankar Kulkarni Dec 03, 2020
The integrated stress response (ISR) is activated during aging. ISR inhibitor (ISRIB) reverses ISR activation in the brain. In old mice, ISRIB reversed spatial memory deficits and ameliorated working memory. In the hippocampus, ISR inhibition rescued the neuronal electrophysiological properties, restored spine density, and reduced interferon and T cell-mediated responses.

Metformin - more to improve the healthspan than lifespan

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Shubhankar Kulkarni
Shubhankar Kulkarni Nov 20, 2020
Metformin is mainly prescribed to diabetics to control the blood glucose levels. There are numerous studies on metformin’s effects beyond the control of diabetes, for example - on cancer, CVD events, mortality, and dementia. The benefits are suggested to be mediated by the “pleiotropic” activities of the drug.

Advantages (as suggested via different studies):
  1. Metformin has a safety and efficacy record not observed with any other diabetic drug.
  2. Metformin is already there. The production and distribution channels are set.
  3. The clinical cohort of male veterans with T2D who were >65 years old included 8,393 metformin users. After 9 years of follow-up, four distinct age-related comorbidity trajectory classes could be identified. In the healthy class, the odds ratio of mortality associated with metformin use was 0.53; in the high-cancer-risk class it was 0.72, in the high-CVD-risk class it was 0.58, and in the high-frailty class it was 0.39, indicating that the last group benefitted most from the drug concerning mortality.
  4. In observational studies (cohort, case-control, and cross-sectional studies), diabetics taking metformin had a lower rate of all-cause mortality and of developing any cancer even compared to the general non-diabetic control population.
Disadvantages:
  1. Metformin is contra-indicated to populations with abnormal kidney function.
  2. The cancer risk with T2D is either not lowered or decreased significantly for patients taking metformin in some studies.

[1]Glossmann HH, Lutz OMD. Metformin and Aging: A Review. Gerontology [Internet]. 2019;65(6):581–90. Available from: https://www.karger.com/Article/FullText/502257

[2]Wang C-P, Lorenzo C, Habib SL, Jo B, Espinoza SE. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. J Diabetes Complications [Internet]. 2017 Apr;31(4):679–86. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1056872716308005

[3]Campbell JM, Bellman SM, Stephenson MD, Lisy. K. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis. Ageing Res Rev [Internet]. 2017 Nov;40:31–44. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1568163717301472

[4]Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP, Schernthaner G, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes, Obes Metab [Internet]. 2014 Nov;16(11):1165–73. Available from: http://doi.wiley.com/10.1111/dom.12354

[5]Xu H, Aldrich MC, Chen Q, Liu H, Peterson NB, Dai Q, et al. Validating drug repurposing signals using electronic health records: a case study of metformin associated with reduced cancer mortality. J Am Med Informatics Assoc [Internet]. 2014 Jul 22; Available from: https://academic.oup.com/jamia/article-lookup/doi/10.1136/amiajnl-2014-002649

[6]Noto H, Goto A, Tsujimoto T, Noda M. Cancer Risk in Diabetic Patients Treated with Metformin: A Systematic Review and Meta-analysis. Biondi-Zoccai G, editor. PLoS One [Internet]. 2012 Mar 20;7(3):e33411. Available from: https://dx.plos.org/10.1371/journal.pone.0033411

The Gut Flora

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Tarik Regad
Tarik Regad Dec 01, 2020


The gut flora is a heterogeneous population of micro-organisms that includes bacteria, fungi, and archaea, and that plays important roles in the digestion and absorbance of food . During the process of aging, the function of beneficial microbes, that provide necessary nutrients for the body tissues, are severally affected, while harmful microbes, that contribute to the process, such as chronic inflammation, flourish. Interestingly, several in vivo studies demonstrated that the transplantation of fecal microbiota from younger mice to older enhanced their health and lifespan .

I wonder if promoting beneficial microbes in older individuals would promote their health and longevity

[1]Guarner, Francisco, and Juan-R. Malagelada. "Gut flora in health and disease." The Lancet 361.9356 (2003): 512-519.

[2]Bárcena, Clea, et al. "Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice." Nature medicine 25.8 (2019): 1234-1242.

[3]Haifer, Craig, Sudarshan Paramsothy, and Rupert W. Leong. "Faecal microbiota transplantation as an elixir of youth." Hepatobiliary Surgery and Nutrition 9.4 (2020): 488.

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Shubhankar Kulkarni
Shubhankar Kulkarni10 months ago
Agreed. The diversity of the gut microbiome changes with age. Centenarians have different gut microbiota (they show an abundance of Verrucomicrobia, Christensenellaceae, and Bifidobacterium), which may be the reason behind their increased lifespan. Improving the gut flora (using probiotics), may be a way to increase lifespan and healthspan. There is another session that describes a similar idea - https://brainstorming.com/ideas/a-fecal-microbiota-transplant-to-treat-aging/9
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Jamila
Jamila 10 months ago
Tarik Regad, that's very true. Slowly but surely, we are finding out that the gut microbiota is important and involved in aging. So far, I don't think there have been studies assessing Fecal Microbiota Transplants or other methods that impact the gut microbiota on the human lifespan. The results from that kind of experiment would be exciting.

I wonder what causes a change in the structure and composition of the gut microbiota as we age.

Epigenetic Diet

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Tarik Regad
Tarik Regad Dec 05, 2020
The epigenome is a set of chemical modifications of the DNA and DNA-related proteins that are involved in regulating gene expression in physiological and pathological conditions, including age-related diseases . Environmental and dietary factors, such as nutritional factors and chemicals, have been directly implicated in altering the epigenome through mechanisms involving DNA methylation and histone modification, leading to the development of abnormalities that affect health and longevity . Interestingly, several studies have demonstrated that bioactive compounds, such as the ones found in fruit, vegetables, and plants, can positively affect the epigenome, contributing to improvements in longevity. These bioactive compounds can influence a relaxed or a closed chromatin form that determines the accessibility of age-related transcription factors to DNA. For instance, resveratrol (Grapes), sulforaphane (Broccoli), and curcumin (Curry) can act at both levels, while others, such as Genistein (Soybeans) can promote a relaxed form of chromatin, and Epigallocatechin-3-gallate (Green tea) can act oppositely by promoting a closed-form of chromatin .

Considering that these bioactive compounds play different roles in regulating the longevity-related epigenome, perhaps, determining the right dietary amounts may further improve their longevity benefits?

[1]Booth, Lauren N., and Anne Brunet. "The aging epigenome." Molecular cell 62.5 (2016): 728-744.

[2]Gallou-Kabani, Catherine, et al. "Nutri-epigenomics: lifelong remodelling of our epigenomes by nutritional and metabolic factors and beyond." Clinical Chemistry and Laboratory Medicine (CCLM) 45.3 (2007): 321-327.

[3]Cosentino, Claudia, and Raul Mostoslavsky. "Metabolism, longevity and epigenetics." Cellular and Molecular Life Sciences 70.9 (2013): 1525-1541.

[4]Hardy, Tabitha M., and Trygve O. Tollefsbol. "Epigenetic diet: impact on the epigenome and cancer." Epigenomics 3.4 (2011): 503-518.

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Jamila
Jamila 10 months ago
Knowing the amounts of specific foods that have longevity benefits would help us out a lot. I found an interesting study showing a high-fat diet and increased body weight was associated with an accelerated epigenetic age in female mice. [1] So, our diet can impact our epigenetic age enormously.

Furthermore, when researchers gave C.elegans supplements of epigallocatechin-3-gallate 50–300 μM, there was an increase in the lifespan. However, 25 μM and more than 300 μM epigallocatechin-3-gallate was not able to increase C. elegans’ lifespan. [2] Therefore, the concentration of the compound is essential too. So, to say the least, our diet is vital.

Reference
1. Sandoval‐Sierra, Jose Vladimir, et al. "Body weight and high‐fat diet are associated with epigenetic aging in female members of the BXD murine family." Aging cell 19.9 (2020): e13207.
2. Xiong, Li-Gui, et al. "Epigallocatechin-3-gallate promotes healthy lifespan through mitohormesis during early-to-mid adulthood in Caenorhabditis elegans." Redox biology 14 (2018): 305-315.

OSK Treatment

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Deru Xu
Deru Xu Dec 20, 2020
In 2006, the team of Japanese scientist Shinya Yamanaka discovered that the four transcription factors "Oct4", "Sox2", "Klf4" and "c-Myc" can induce stem cell regeneration. Shinya Yamanaka also won the 2012 Nobel Prize in Physiology or Medicine. However, with the deepening of this research, scientists have discovered that the regenerative superpower of this cell can induce teratomas and may even lead to the death of experimental animals. On December 2, 2020, "Nature" published an article by Professor David Sinclair and others. After repeated experiments, David Sinclair's team found that "c-Myc factor" was the main cause of teratoma. Therefore, David Sinclair's team eliminated "c-Myc factor" in the experiment and only retained "Oct4" and "Sox2" , "Klf4" three transcription factors, the team called this new combination OSK.

Researchers found that after 4 weeks of OSK treatment in 12-month-old middle-aged mice, nearly 90% of retinal ganglion cells expressing abnormal genes due to aging were restored to a young level. The methylation physiological age test also showed , The mouse’s biological age clock is turning in the opposite direction .

Advantages:
  1. Live reprogramming
  2. Nerve regeneration
  3. No carcinogenicity

[1]Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., . . . Sinclair, D. A. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature, 588(7836), 124-129. doi:10.1038/s41586-020-2975-4

[2] Sarkar, T.J., Quarta, M., Mukherjee, S. et al. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat Commun 11, 1545 (2020).

[3]Goldberg, Jeffrey L et al. “Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity.” Neuron vol. 33,5 (2002): 689-702. doi:10.1016/s0896-6273(02)00602-5

[4]Park, Kevin Kyungsuk et al. “Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway.” Science (New York, N.Y.) vol. 322,5903 (2008): 963-6. doi:10.1126/science.1161566

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Jamila
Jamila 10 months ago
Hi Deru Xu.

OSK reprogramming is definitely promising. There are loads of research papers that support cellular reprogramming as a lifespan extension tool. The biggest issue with prolonged cellular reprogramming is the formation of teratomas and loss of somatic memory. Ultimately, prolonged cellular reprogramming leads to death in mice. [1] We want to revert cells to a more youthful state using cellular reprogramming, but we don't want them to lose their cellular identity or cause the formation of teratomas.

Researchers have found a way to address these problems by using partial reprogramming instead of prolonged reprogramming. In a study by Ocampo and Colleagues, the researchers used partial reprogramming in mice. This resulted in the reversal of aging hallmarks and improvement in the mice's lifespan without the formation of teratomas. [1]

Being able to control in vivo reprogramming is crucial because prolonged cellular reprogramming won't suffice. There is a range of different methods that can be used to give temporal control over cellular reprogramming. In a previous brainstorming session, we discussed other methods that could be used to achieve cellular reprogramming: https://brainstorming.com/sessions/what-methods-can-be-used-to-control-in-vivo-cellular-reprogramming/26.

Reference
Ocampo, Alejandro, et al. "In vivo amelioration of age-associated hallmarks by partial reprogramming." Cell 167.7 (2016): 1719-1733.

PGE2-EP2 binding inhibitors/ blockers

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Shubhankar Kulkarni
Shubhankar Kulkarni Jan 21, 2021
Recently, neurologists at Stanford University discovered that the aging of immune cells that leads to inflammatory age-related diseases can be reversed. The levels of a hormone called prostaglandin E2 (PGE2) have been found to rise with age and PGE2 promotes inflammatory activity in immune cells. Older macrophages produce significantly more PGE2 than young ones. Also, aging macrophages express a greater number of surface EP2 receptors that bind to PGE2 leading to a positive-feedback loop.

The authors showed that when you inhibit this PGE2-EP2 binding mechanism in vitro, the macrophages lose their pro-inflammatory phenotype and the old cells seem to rejuvenate. In vivo, the authors showed that Inhibiting the PGE2-EP2 binding mechanism (using a drug that blocks PGE2-EP2 binding) in aged mouse models of the cognitive decline resulted in the reversal of cognitive decline, and the then cognitive abilities were comparable to those of young mice. It restored systemic and brain inflammatory states, hippocampal synaptic plasticity, as well as spatial memory. It was interesting that although the drug could not cross the blood-brain barrier and it showed an effect on cells outside the brain, cognitive improvements and reductions in neural inflammation were detected (in the brain).

The drug, however, is not ready for clinical use in humans currently. Also, such reversal of the aged macrophages by blocking PGE2-EP2 binding needs to be replicated and confirmed.

[1]Minhas, P.S., Latif-Hernandez, A., McReynolds, M.R. et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature (2021). https://doi.org/10.1038/s41586-020-03160-0

Mitochondrial ORF of the 12S rRNA type-c (MOTS-c) promotes healthspan and lifespan

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Shubhankar Kulkarni
Shubhankar Kulkarni Jan 22, 2021
MOTS-c is a mitochondrial-derived peptide, which increases during exercise. It further relays the beneficial effects of exercise. Recently, it was shown that young, middle-age, and old mice treated with MOTS-c have significantly improved physical performance and an enhanced adaptation to metabolic stress in a myoblast cell line.

The endurance capacity of middle-aged mice treated with MOTS-c was comparable to that of young mice treated with MOTS-c although the untreated young mice did better than the untreated middle-aged mice. MOTS-c treatment also improved morphometric parameters like body weight, percent fat mass, and percent lean mass in the mice. It reduced the food intake and increased the lifespan of the mice beyond 36 months (lifespan of untreated mice was about 34.5 months).

The same group had previously reported that MOTS-c treatment prevented diet-induced obesity and insulin resistance and reversed age-dependent skeletal muscle insulin resistance in mice. The authors also mention that the exceptionally long-lived Japanese population has a mitochondrial DNA SNP that expresses a functional variant of MOTS-c.

Although the peptide is currently at the research stage, it holds the potential to be one of the mainstream longevity therapies in the future.

[1]Reynolds, J.C., Lai, R.W., Woodhead, J.S.T. et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun 12, 470 (2021). https://doi.org/10.1038/s41467-020-20790-0

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Jamila
Jamila 9 months ago
Hi Shubhankar Kulkarni, thanks for the contribution.

It seems that MOTS-C has quite beneficial effects in ageing mice. I know the peptide is in its early stages right now, but I do wonder if MOTS-C has been used in any other animal models yet with similar anti-ageing results.

Interestingly, the SNP (MT-1382 A>C) is found in 5-10% of East Asian populations. Apparently, having the C allele increases your risk of diabetes. Therefore, the authors suggest that MT-1382 A>C polymorphism may be a risk factor for type 2 diabetes in Eastern Asian populations. [1] Leading on from that, it's intriguing that long-lived individuals from the Japanese population had MT-1382 A>C. I wonder if non-Japanese populations also carry this SNP, and are they long-lived or are the effects exclusively observed in the Japanese population.

Reference
1. Kim, Su-Jeong, et al. "Mitochondrial-derived peptides in ageing and age-related diseases." GeroScience (2020): 1-9.

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Shubhankar Kulkarni
Shubhankar Kulkarni9 months ago
Jamila Wow! We have found contradictory reports. At least both reports agree that the wild-type MOTS-c is a pro-longevity factor.

I could think of a couple of reasons for this contradiction:
1. About 5-10% is not a significant enough proportion to drive the results in their favor. Hence, the study that I cited may have incidentally considered more A-allele having participants and since having the A allele is not a risk factor for type 2 diabetes, hence the result.
2. Also, the observed phenotype in people having the C allele seems to be gender-dependent. In another study, the authors found a higher prevalence of type 2 diabetes in men having the C allele than those having the A allele but no such difference was observed in females. [1]
3. Another paper suggests that the C allele is actually associated with exceptional longevity. [2] I think any claim around MT-1382 A>C needs more studies backing it. In support of this, another study suggests that type 2 diabetes is associated with equal (actually slightly more) longevity (expected lifespan) compared to the non-diabetic population. [3]

Reference:
1. Zempo, H., Fuku, N., Nishida, Y., Higaki, Y., Naito, H., Hara, M. and Tanaka, K. (2016), Relation between type 2 diabetes and m.1382 A>C polymorphism which occurs amino acid replacement (K14Q) of mitochondria‐derived MOTS‐c. The FASEB Journal, 30: 956.1-956.1. https://doi.org/10.1096/fasebj.30.1_supplement.956.1
2. Fuku, N., Pareja‐Galeano, H., Zempo, H., Alis, R., Arai, Y., Lucia, A. and Hirose, N. (2015), The mitochondrial‐derived peptide MOTS‐c: a player in exceptional longevity?. Aging Cell, 14: 921-923. https://doi.org/10.1111/acel.12389
3. Tachkov K, Mitov K, Koleva Y, et al. Life expectancy and survival analysis of patients with diabetes compared to the non diabetic population in Bulgaria. PLoS One. 2020;15(5):e0232815. Published 2020 May 11. doi:10.1371/journal.pone.0232815


Here is a study in humans that associates MOTS-c with anti-aging:
1. D’Souza RF, Woodhead JST, Hedges CP, Zeng N, Wan J, Kumagai H, Lee C, Cohen P, Cameron-Smith D, Mitchell CJ, Merry TL. Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition. Aging (Albany NY). 2020; 12:5244-5258. https://doi.org/10.18632/aging.102944


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Jamila
Jamila 9 months ago
Shubhankar Kulkarni very interesting! We definitely need more studies in regards to the MT-1382 A>C SNP 😀

NAD+ and nervous system, cancer, liver function, kidney function, skeletal muscle, heart function

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Deru Xu
Deru Xu Feb 05, 2021
NAD+ and the nervous system

Sirtuins are deacylases that rely on NAD+ and are traditionally believed to be related to calorie restriction and aging in mammals . These proteins also play an important role in maintaining the health of neurons during aging.

In the process of neural development, SIRT1 plays an important role in structure, promoting axonal growth, neurite growth and dendritic branching through the Akt-GSK3 pathway. The development of synapses and the regulation of synaptic strength are crucial to the formation of memory, and sirtuins proteins play an important role in this process, whether in physiology or after injury. SIRT1 regulates the expression of brain-derived neurotrophic factor (BDNF).
This is important for the formation and long-term enhancement of synapses.In the development of neurological diseases, SIRT1 plays a protective role in a variety of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and motor neuron disease.

Drugs that activate SIRT1 may provide a promising way to treat these diseases.

NAD+ and cancer

NMNAT3 overexpression increases mitochondrial NAD+ levels and inhibits the growth of glioblastoma cells; supplementation of NA or NAM can inhibit tumor growth and multi-organ tumor metastasis in SCID mice.

Increasing NAD+ will also increase SIRT1 The activity of SIRT6 and SIRT6 both inhibit tumors by down-regulating β-catenin signaling and down-regulating glycolysis. After reducing tumor NAD+ levels, as the ability of PARPs to repair DNA damage decreases, the sensitivity of cancer cells/tissues to chemotherapy drugs will increase. It will be very important to further test the effects of NAD+ supplements in standard cancer models.

However, there are also contradictions and concerns: NAD+ promotes DNA repair and angiogenesis, and may help cancer cells grow.

Increasing eNAMPT can promote the increase of NAD+, resist aging and extend healthy life. The hypothalamus is the high-order control center of mammalian aging. The study hypothesized that eNAMPT secreted by adipose tissue plays a key role in affecting the aging process and ultimate life span. In this study, adipose tissue-specific Nampt knock-in protein (ANKI) mice were constructed. The results showed that elderly ANKI mice maintained young levels of circulating eNAMPT and increased NAD + levels in a variety of tissues (including hypothalamus, hippocampus, pancreas and retina), showing improved physical activity, sleep quality, cognitive function, and glucose metabolism And the photoreceptor function is significantly improved. Surprisingly, injection of eNAMPT-containing EVs purified from young mice or cultured adipocytes can enhance the mobility of older mice and extend their lifespan.

NAD+ and liver function

Inhibiting NAMPT will make the liver steatosis caused by high-fat diet more serious, and overexpression of NAMPT significantly improves liver lipid accumulation; this regulatory effect is achieved through " Inhibit NAMPT→reduce NAD+→inhibit SIRT1→decrease the deacetylation of SREBP1→decrease SREBP1 activity→up-regulate FASN and ACC expression".

Under normal circumstances, due to obesity and aging, the level of NAMPT decreases and the level of CD38 increases, resulting in a two-fold decrease in steady-state NAD+ levels in middle age.

Improving glucose homeostasis and mitochondrial dysfunction, improving liver health, enhance its regeneration ability, and protecting the liver from Liver toxicity damage.

NAD+ and kidney function

Activation of SIRT1 and SIRT3 by NAD+ supplementation protects high glucose-induced renal mesangial cell hypertrophy, while mice treated with NMN protect cisplatin-induced acute kidney injury (AKI) in a SIRT1-dependent manner.

Mice supplemented with NAM can stimulate the secretion of the renal protective prostaglandin PGE2 and improve renal function after ischemia

NAD+ and skeletal muscle

Treating elderly mice with NMN (500 mg/kg/day ip. for 7 consecutive days) can increase mitochondrial function, increase ATP production, reduce inflammation, and transform glycolytic type II muscle into oxidized fibrous muscle.

NAD+ and heart function

SIRT3-KO mice will develop fibrosis and myocardial hypertrophy when they are 13 months old. As they age, their condition will worsen. NMN treatment can reverse this decline.
NAMPT overexpression or NMN treatment can significantly prevent pressure overload and ischemia-reperfusion injury. Reduce the infarct size by about 44%.

[1]Campisi, J., Kapahi, P., Lithgow, G.J. et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature 571, 183–192 (2019).

[2]Mitsukuni Yoshida,Akiko Satoh,Jonathan B. Lin,Kathryn F. Mills,Yo Sasaki,Nicholas Rensing,Michael Wong,Rajendra S. Apte,Shin-ichiro Imai. Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice[J]. Cell Metabolism,2019,30(2).

Senolytic drugs to remove senescent cells.

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Jamila
Jamila Feb 05, 2021
Senescent cells are cells that have stopped proliferating. Senescence can be induced by cellular stress, telomere shortening, inflammation, etc. These senescent cells arise with the aging phenotype, i.e., as you age, you get more senescent cells. Researchers have found a way to eliminate these damaging senescent cells by using Senolytics. Senolytics are a special class of drugs that can remove senescent cells without damaging healthy cells.

Dasatinib and quercetin are a well-studied cocktail of Senolytic drugs. They are known to reduce senescent cells and any associated proinflammatory cytokines. In one study, researchers used dasatinib and quercetin in mice. They found that the Senolytic cocktail improved physical function and also boosted survival by 36% in aged mice and young mice with senescent cell transplants.

[1]Collado, Manuel, Maria A. Blasco, and Manuel Serrano. "Cellular senescence in cancer and aging." Cell 130.2 (2007): 223-233.

[2]Xu, Ming, et al. "Senolytics improve physical function and increase lifespan in old age." Nature medicine 24.8 (2018): 1246-1256.

An increase in the levels of LB1 or a decrease in those of SUN1 to decline aging in neural stem cells

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Shubhankar Kulkarni
Shubhankar Kulkarni Feb 25, 2021
Neural stem cells generate neurons throughout life in the hippocampal region of the brain. Neurogenesis drops with advancing age and it is associated with a decline in hippocampal memory function. A research group recently showed that the nuclear lamina protein lamin B1 (LB1) levels downregulated (intracellularly) with age in mouse hippocampal NSCs and the protein levels of SUN-domain-containing protein 1 (SUN1), implicated in Hutchinson-Gilford progeria syndrome, increased. Increasing the levels of LB1 and decreasing those of SUN1 in aged NSCs restored the strength of the endoplasmic reticulum diffusion barrier that segregates aging factors in proliferating NSCs. Therefore, an increase in the levels of LB1 or a decrease in those of SUN1 can be a therapy to reduce age-related decline in the proliferation of neural stem cells.

[1]Muhammad Khadeesh bin Imtiaz, Baptiste N. Jaeger, Sara Bottes, Raquel A.C. Machado, Mojca Vidmar, Darcie L. Moore, Sebastian Jessberger. Declining lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity, Cell Stem Cell, 2021, ISSN 1934-5909, https://doi.org/10.1016/j.stem.2021.01.015. https://www.sciencedirect.com/science/article/pii/S1934590921000151

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