Potential Interventions to Ameliorate Degenerative Aging      

By Ilia Stambler

A long road ahead

The interventions into the degenerative aging process are still in their infancy.1 A long effortful road will yet need to be traveled from basic research on cell cultures and animal models to effective, safe and widely available human therapies.2 Many dangers to human health (such as overdose and overstimulation) and many unsubstantiated false claims yet await on this road, that need to be guarded against as much as possible.3 Yet vast promising research is progressing, especially as regards potential pharmaceutical interventions into the aging process.4,5 Below are some examples.

1.    Targeting Aging with Metformin

On November 28, 2015, the FDA approved the testing of Metformin, a decades-old anti-diabetic (blood sugar reducing) medication (of the biguanide class), as the first drug to treat degenerative aging, rather than particular diseases or symptoms, as a way to prevent general age-associated multimorbidity (postponing the emergence of several age-related diseases and dysfunctions at once).6,7 Though the study concept may be seminal, as of this writing in 2017, sufficient funding for this trial has been lacking.

2.    Anti-aging adjuvant therapy

On November 25, 2015, the FDA approved an adjuvant therapy (the adjuvant MF59, made with squalene oil, developed by Novartis) for a flu vaccine to boost immune response in older persons. This development goes beyond “a drug against a disease” model, but seeks an appropriate regulatory framework to support the underlying health of older persons, using “adjuvant” (i.e. “supportive/additional”) therapy.8

3.    Rapamycin and rapalogs

The immunosuppressant drug Rapamycin, believed to mimic the healthspan-extending effects of calorie restriction (CR-mimetic), has been shown to produce improvements of energy metabolism, and to extend lifespan and delay aging in mice, and was also effective against particular aging-related diseases, such as Alzheimer’s disease, in human studies. Further research is done on Rapamycin’s analogs – the so-called “rapalogs,” potentially with less side effects.9 

4.     Blood transfusion

By splicing the circulatory systems of animals (mice) together, via the process of “parabiosis,” young blood was indicated to have rejuvenating effects on old tissues, including the heart, brain, and muscle tissues, with improved strength and cognitive ability. Some of the hypothetical rejuvenating factors included: Notch signaling activators, deactivation of the transforming growth factor (TGF)-β that blocks cell division, oxytocin, and Growth Differentiation Factor 11 (GDF11). In September 2014, a clinical trial by Alkahest in Menlo Park, California, became the first to start testing the benefits of young blood and young plasma in older people with Alzheimer’s disease.10 However, in a more recent evaluation, it was suggested that young blood does not contain rejuvenating substances, but rather the old blood contains pro-aging, growth-inhibiting substances (or toxic waste products) that can accelerate aging in younger animals, and these can be partly diluted or neutralized by the infusions of young blood. The search has begun for such pro-aging, growth-inhibiting substances and ways of their neutralization.11

5.    Senescent cell elimination

A new class of drugs – the “senolytics” capable of eliminating senescent cells and the accompanying pathologies – are being developed, in Mayo Clinic, Rochester, Minnesota, and elsewhere.12 Thus, the combinations of the “senolytic” drugs Dasatinib and Quercetin proved effective against senescent human cells and in a mouse model. Together these drugs were able to reduce senescent cell burden, extend healthspan and improve physical exercise capacity in old mice, reducing their osteoporosis and other age-related pathologies.13 Senescent cells can also be eliminated by immunological means, such as vaccines, antibodies and killer T cells.14

6.    Sirtuin activation and NAD replacement therapy

Resveratrol, a natural polyphenolic compound, among other sources found in red wine, has demonstrated the ability to up-regulate Sirtuin 1 (SIRT1) – an acknowledged prolongevity enzyme15important for enhanced stress response, DNA stabilization, cardiovascular protection, improved cognitive function and synaptic plasticity, and suppressing inflammation.16 SIRT1 expression is generally related to the levels of energy metabolism, as indicated by NAD/NADH levels, which have also become targets for diverse pharmaceutical interventions (NAD replacement therapy).17 Additional forms of NAD replacement therapy (e.g. with nicotinamide riboside – NR – a form of vitamin B3, and nicotinamide mononucleotide – NMN)18,19 and activators of other Sirtuin enzymes (such as SIRT6)20,21 are being developed.

7.    pH and Redox manipulation

Dichloroacetate and bicarbonate represent a class of compounds and therapies that may have systemic effects on tissue redox and pH state, with broad implications for the aging process22 and derivative pathologies, such as cancer.23

8. Regenerative medicine – extracorporeal and intracorporeal cell and tissue growth and replacement

Generally, regenerative medicine, using stem cells of various origins to rebuild, “regenerate” or improve the function of worn out and aging organs and tissues, can be promising for combating the degenerative pathologies of aging.24 Even entire “replacement organs and tissues” can be grown outside of the body – using such methods as growing tissues on biodegradable scaffolds, 3D tissue printing, bioreactors or self-organization — to “replace” the worn out and aging body parts.25 Yet, recently a very promising direction in regenerative medicine has emerged – the induction of regeneration within the body by pharmacological means (e.g. using inhibitors of prostaglandin breakdown, thus promoting cell proliferation).26

9.    Immune organ regeneration

Of special importance for regenerative medicine against aging-related degeneration is the ability to regenerate the thymus gland (that produces the immune T-cells that play the crucial role for the immune defense). This importance derives from the fact that such an ability could dramatically improve therapy not only for aging-related non-communicable chronic diseases (such as heart disease and neurodegenerative diseases that are strongly related to altered immune response), but also help combat infectious, communicable diseases (like AIDS, Herpes and Influenza) thanks to improved immunity. Such regenerative ability for the thymus was shown by genetic engineering interventions (e.g. using over-expression of the FOXO gene)27 and even pharmaceutical treatments (e.g. using the FGF21 hormone).28

10. Telomere extension to increase cell replication

The extension of the telomere end points of the chromosomes, thus increasing the number of cell replications, by such means as genetically engineered overexpression of the telomere-repairing enzyme – telomerase, and even by some pharmacological stimulators of telomerase activity, have been associated with increased lifespan and reduced pathology in animal models.29,30

11. Improving mitochondrial function

There have been many methods investigated for improving mitochondrial function and cellular respiration. Thus anti-oxidant molecules attached to positively charged ions (cations) have been targeted into mitochondria to eliminate oxidative damage at its origin (the SkQ ions).31 In another approach, chemical compounds (in particular suppressors of the IIIQsite of the respiratory chain in the mitochondria) have been identified that can block the production of certain free radicals in cells, without changing the energy metabolism of these cells.32 A large additional array of boosters of mitochondrial activity and cellular respiration has been proposed, e.g. methylene blue, the naphthoquinone drug β-lapachone, supplementation with various components of the respiratory oxidative phoshorylation system – such as CoQ10, pyruvate, succinate, vitamins C and K, quercetin, various other anti-acidic, anti-toxic, and anti-oxidant substances.33

12. Immune-modulating substances

Anti-inflammatory medications have been widely tested to diminish aging-related degenerative pathologies, such as neurodegenerative pathologies, and to extend healthy lifespan in animal models.34 But also pro-inflammatory effects have been shown to be important for tissue regeneration.35

13. Cross-link breakers

Diverse means are being developed to dissolve macro-molecular (cross-linked) aggregates that “clog” cell machinery. Some approaches include stimulation of cell autophagy that can help remove such aggregates (e.g. by introducing Beclin protein). Various “AGE-breakers” are being developed. These are, as a rule, small molecules capable of breaking “Advanced Glycation Endproducts (AGE)” that are chiefly responsible for the formation of macromolecular aggregates (such as glucosepane, one of the most common forms of cross-linked AGE products in collagen). Some of the therapeutic means against cross-linked aggregates include chelators (removing the metal ions that are important for the formation of the cross-links), enzymatic clearance (oxidoreductive depolymerization of the aggregates by enzymes), immunoclearance (using immune mechanisms, e.g. antibodies, to remove the aggregates), etc.36,37 Yet, it needs to be noted that macromolecular aggregates, in certain amounts and under certain circumstances, may have a necessary function in the body too.38 Removing too much of them and in wrong places may do more damage than good.

14. Nutrient balance

Keeping the body chemistry in balance is hoped to be achieved by supplementing deficient elements in the diet (e.g. vitamins, microelements, other essential nutrients), while eliminating excessive and therefore toxic elements (by such means as chelators, enterosorbents, dietary restriction, enhanced elimination).39 But what is “the balance”? How much is “too much” or “too little”? The guiding rule is always: “The dose makes the poison.”1 Dietary interventions, that are being tested, include dietary restrictions of various kinds (mainly protein restriction and calorie restriction) that have been associated with extended lifespan in animal models and some health benefits in humans.40 Also new ways are being sought to enrich the “microbiome” (intestinal bacteria populations) for healthy longevity,41 for example using probiotic diets – the idea that goes back to the origins of scientific aging research, over a century ago.42

15. Epigenetic rejuvenation

Epigenetics (acquired or heritable changes in gene function without changes in DNA sequence), has been increasingly investigated and manipulated for its effects on aging and aging-related diseases, and their amelioration, at the level of the entire organism as well as particular tissues, for example, using demethylating agents, small interfering RNAs (siRNAs) and micronutrients as potential therapeutic agents.43-45

16. Nanomedicine

Interventions into degenerative aging are now beginning to reach the “nano” level (using molecular structures and devices up to several hundred nanometers). Some of the uses of nanomedicine against degenerative aging include nanoparticles, such as Buckminsterfullerene or “bucky-ball” C60, with assumed antiviral, antioxidant, anti-amyloid, immune-stimulating and other therapeutic activities, and some reported lifespan-extending results in mice.46 Moreover, there even have been announced the first operating medical nanorobots, mainly intended to assist in precise drug delivery, acting as prototypes of artificial immune cells.47 These nanodevices were mainly intended to eliminate cancer cells, but could also be used to eliminate other types of cells, e.g. senescent cells. In another area of development, oxygenated micro-particles seem to be very promising for life extension, especially in critical conditions, as oxygen deprivation is the main (or even the ultimate) cause of death.48

17. Physical interventions

Anti-aging and life-extending interventions do not necessarily need to be chemical and biological, but can also be physical, in particular as relates to various resuscitation technologies (hypothermia and suspended animation,49,50 oxygenation,51-53 electromagnetic stimulation54-56). Such technologies represent probably the most veritable means for life extension, demonstrably saving people from an almost certain death. But similar principles could perhaps be used for more preventive treatments and in less acute cases.

18. Biomarkers of aging

It seems to be impossible to speak of “treating” or “curing degenerative aging” without the ability to diagnose this condition and to reliably assess the effectiveness of interventions against it.2,3,57-59 Hence a wide array of biomarkers and clinical end points are being sought to diagnose degenerative aging and aging-related ill health, and to determine correct “biological age.”60-63 Clinically applicable and scientifically grounded diagnostic criteria and definitions for aging may also have profound encouraging implications for the regulation and promotion of research, development, application and distribution of anti-aging and life-extending and healthspan-extending therapies.64,65

Acknowledgement

I thank Steve Hill and Kevin Perrott for their suggestions.

References and notes

1. Ilia Stambler, A History of Life-Extensionism in the Twentieth Century, Longevity History, 2014, http://www.longevityhistory.com/.
2. Ilia Stambler, “Human life extension: opportunities, challenges, and implications for public health policy,” in Alexander Vaiserman (Ed.), Anti-aging Drugs: From Basic Research to Clinical Practice, Royal Society of Chemistry, London, 2017, pp. 535-564.
3. Ilia Stambler, “Recognizing degenerative aging as a treatable medical condition: methodology and policy,” Aging and Disease, 8(5), 2017, http://www.aginganddisease.org/EN/10.14336/AD.2017.0130.
4. Kunlin Jin, James W. Simpkins, Xunming Ji, Miriam Leis, Ilia Stambler, “The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population,” Aging and Disease, 6, 1-5, 2015, http://www.aginganddisease.org/EN/10.14336/AD.2014.1210.
5. Ilia Stambler, “Stop Aging Disease! ICAD 2014,” Aging and Disease, 6(2), 76-94, 2015, http://www.aginganddisease.org/EN/10.14336/AD.2015.0115.
6. “Dr. Nir Barzilai on the TAME Study,” Healthspan Campaign, April 28, 2015, http://www.healthspancampaign.org/2015/04/28/dr-nir-barzilai-on-the-tame-study/ .
7. Stephen S. Hall, “A trial for the ages,” Science, 349(6254), 1275-1278, 2015, http://www.sciencemag.org/news/2015/09/feature-man-who-wants-beat-back-aging;
Sarah Knapton, "World's first anti-ageing drug could see humans live to 120," The Telegraph, November 29, 2015, http://www.telegraph.co.uk/science/2016/03/12/worlds-first-anti-ageing-drug-could-see-humans-live-to-120/;
John C. Newman, Sofiya Milman, Shahrukh K. Hashmi, Steve N. Austad, James L. Kirkland, Jeffrey B. Halter, Nir Barzilai, “Strategies and Challenges in Clinical Trials Targeting Human Aging,” Journal of Gerontology: Biological Sciences, 71(11), 1424-1434, 2016, https://academic.oup.com/biomedgerontology/article/71/11/1424/2577175/Strategies-and-Challenges-in-Clinical-Trials.
8. Robert Preidt, “FDA Approves Flu Shot to Boost Immune Response. Vaccine can be used in seniors, who are often hit hardest by illness,” WebMD News from HealthDay, November 25, 2015, http://www.webmd.com/cold-and-flu/news/20151125/fda-approves-first-flu-shot-with-added-ingredient-to-boost-immune-response.
9. Arlan Richardson, Veronica Galvan, Ai-Ling Linc, Salvatore Oddo, “How longevity research can lead to therapies for Alzheimer’s disease: The rapamycin story,” Experimental Gerontology, 68, 51-58, 2015, http://www.sciencedirect.com/science/article/pii/S0531556514003490.
10. Megan Scudellari, “Ageing research: Blood to blood,” Nature, 517(7535), January 21, 2015, http://www.nature.com/news/ageing-research-blood-to-blood-1.16762.
11. Brett Israel, "Young blood does not reverse aging in old mice, UC Berkeley study finds," Berkeley News, November 22, 2016, http://news.berkeley.edu/2016/11/22/young-blood-does-not-reverse-aging-in-old-mice-uc-berkeley-study-finds/, based on Justin Rebo, Melod Mehdipour, Ranveer Gathwala, Keith Causey, Yan Liu, Michael J. Conboy, Irina M. Conboy, "A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood," Nature Communications, 7, 13363, 2016, http://www.nature.com/articles/ncomms13363.
12. Nicholas Wade, "Purging Cells in Mice Is Found to Combat Aging Ills," The New York Times, November 2, 2011,
http://www.nytimes.com/2011/11/03/science/senescent-cells-hasten-aging-but-can-be-purged-mouse-study-suggests.html?_r=0, based on Darren J. Baker, Tobias Wijshake, Tamar Tchkonia, Nathan K. LeBrasseur, Bennett G. Childs, Bart van de Sluis, James L. Kirkland, Jan M. van Deursen, “Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders,” Nature, 479(7372), 232-236, 2011, https://www.nature.com/nature/journal/v479/n7372/full/nature10600.html.
13. Yi Zhu, Tamara Tchkonia, Tamar Pirtskhalava, ..., James L Kirkland, “The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs,” Aging Cell, 14, 644–658, 2015, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078/.
14. Yossi Ovadya, Valery Krizhanovsky, “Senescent cell death brings hopes to life,” Cell Cycle, 16(1), 9-10, 2017, http://www.tandfonline.com/doi/full/10.1080/15384101.2016.1232088.
15. Carles Cantó, Johan Auwerx, “Targeting Sirtuin 1 to Improve Metabolism: All You Need Is NAD+?” Pharmacological Reviews, 64(1), 166-187, 2012, http://pharmrev.aspetjournals.org/content/64/1/166.
16. Maheedhar Kodali, Vipan K. Parihar, Bharathi Hattiangady, Vikas Mishra, Bing Shuai, Ashok K. Shetty, “Resveratrol Prevents Age-Related Memory and Mood Dysfunction with Increased Hippocampal Neurogenesis and Microvasculature, and Reduced Glial Activation,” Scientific Reports, 5, 8075, 2015, http://www.nature.com/articles/srep08075.
17. Karen Weintraub, “The Anti-Aging Pill,” MIT Technology Review, February 3, 2015, http://www.technologyreview.com/news/534636/the-anti-aging-pill/
18. Samuel A. J. Trammell, Mark S. Schmidt, Benjamin J. Weidemann, Philip Redpath, Frank Jaksch, Ryan W. Dellinger, Zhonggang Li, E. Dale Abel, Marie E. Migaud, Charles Brenner, “Nicotinamide riboside is uniquely and orally bioavailable in mice and humans,“ Nature Communications, 7, 12948, 2016, http://www.nature.com/articles/ncomms12948.
19. “A Study to Evaluate Safety and Health Benefits of Basis™ Among Elderly Subjects,” 15BSHE, Sponsor: Elysium Health, at ClinicalTrials.gov, First received: February 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02678611;
Kazuo Tsubota, "The first human clinical study for NMN has started in Japan," NPJ Aging and Mechanisms of Disease, 2, 16021, 2016, https://www.nature.com/articles/npjamd201621.
20. Heidi Ledford, “Sirtuin protein linked to longevity in mammals. Male mice overproducing the protein sirtuin 6 have an extended lifespan,” Nature News, 22 February 2012, based on Yariv Kanfi, Shoshana Naiman, Gail Amir, Victoria Peshti, Guy Zinman,            Liat Nahum, Ziv Bar-Joseph, Haim Y. Cohen, “The sirtuin SIRT6 regulates lifespan in male mice,” Nature, 483, 218–221, 2012, http://www.nature.com/news/sirtuin-protein-linked-to-longevity-in-mammals-1.10074.
21. Weijie You, Dante Rotili, Tie-Mei Li, Christian Kambach, Marat Meleshin, Mike Schutkowski, Katrin F. Chua, Antonello Mai, Clemens Steegborn, “Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules,” Angewandte Chemie International Edition, 56(4), 1007-1011, 2017.
22. Khachik Muradian, “’Pull and push back’ concepts of longevity and life span extension,” Biogerontology, 14(6), 687-691, 2013.
23. Ian F. Robey, Natasha K. Martin, “Bicarbonate and dichloroacetate: Evaluating pH altering therapies in a mouse model for metastatic breast cancer,” BMC Cancer, 11, 235, 2011, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125283/.
24. Jennifer L. Olson, Anthony Atala, James J. Yoo, “Tissue Engineering: Current Strategies and Future Directions,” Chonnam Medical Journal, 47(1), 1-13, 2011, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214857/.
25. Giuseppe Orlando, Shay Soker, Robert J. Stratta, Anthony Atala, “Will Regenerative Medicine Replace Transplantation?” Cold Spring Harbor Perspectives in Medicine, 3(8), a015693, 2013, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721273/.
26. “New drug triggers tissue regeneration: Faster regrowth and healing of damaged tissues,” Science Daily, June 11, 2015, http://www.sciencedaily.com/releases/2015/06/150611144438.htm, based on Yongyou Zhang, Amar Desai, Sung Yeun Yang, ..., Sanford D. Markowitz, “Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration,” Science, 348(6240), aaa2340, 2015.
27. “Living organ regenerated for first time: Thymus rebuilt in mice,” Science Daily, April 8, 2014, http://www.sciencedaily.com/releases/2014/04/140408115610.htm, based on Nicholas Bredenkamp, Craig S. Nowell, C. Clare Blackburn, “Regeneration of the aged thymus by a single transcription factor,” Development, 141(8), 1627-1637, 2014.
28. “Life-extending hormone bolsters the body’s immune function,” Science Daily, January 12, 2016, http://www.sciencedaily.com/releases/2016/01/160112093545.htm, based on Yun-Hee Youm, Tamas L. Horvath, David J. Mangelsdorf, Steven A. Kliewer, Vishwa Deep Dixit, “Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution,” Proceedings of the National Academy of Sciences USA, 113(4), 1026-1031, 2016.
29. Ian Sample, “Harvard scientists reverse the ageing process in mice – now for humans,” Guardian, November 28, 2010, http://www.guardian.co.uk/science/2010/nov/28/scientists-reverse-ageing-mice-humans, based on Mariela Jaskelioff, Florian L. Muller, Ji-Hye Paik, ..., Ronald A. DePinho, “Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice,” Nature, 469, 102-106, 2011 (first published on line on November 28, 2010).
30. Christian Bär, Maria A. Blasco, “Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases,” F1000Research 2016, 5 (F1000 Faculty Reviews), 89, doi:10.12688/f1000research.7020.1, http://f1000research.com/articles/5-89/v1.
31. Vladimir P. Skulachev, Vladimir N. Anisimov, Yuri N. Antonenko, Lora E. Bakeeva, Boris V. Chernyak, Valery P. Erichev, Oleg F. Filenko, Natalya I. Kalinina, Valery I. Kapelko, “An attempt to prevent senescence: a mitochondrial approach,” Biochimica et Biophysica Acta, 1787(5), 437-61, 2009, http://www.sciencedirect.com/science/article/pii/S0005272808007573.
32. Eric Bender, “Stopping free radicals at their source,” Novartis Institute for Biomedical Research, September 22, 2015, https://www.nibr.com/stories/discovery/stopping-free-radicals-their-source, based on Adam L. Orr, Leonardo Vargas, Carolina N. Turk, ..., Martin D. Brand, “Suppressors of superoxide production from mitochondrial complex III,” Nature Chemical Biology, 11(11), 834-836, 2015.
33. Eric A. Schon, Salvatore DiMauro, “Medicinal and Genetic Approaches to the Treatment of Mitochondrial Disease,” Current Medicinal Chemistry, 10, 2523-2533, 2003, http://homepages.ihug.co.nz/~Smconnell/Medicinal%20and%20Genetic%20Approaches%20to%20Mitochonrial%20Disease.pdf.
34. Buck Institute, “Could ibuprofen be an anti-aging medicine?” December 11, 2014, http://www.buckinstitute.org/buck-news/could-ibuprofen-be-an-anti-aging-medicine, based on Chong He, Scott K. Tsuchiyama, Quynh T. Nguyen, ..., Brian K. Kennedy, Michael Polymenis, “Enhanced Longevity by Ibuprofen, Conserved in Multiple Species, Occurs in Yeast through Inhibition of Tryptophan Import,” PLoS Genetics, 10(12), e1004860, 2014.
35. Michael Karin, Hans Clevers, “Reparative inflammation takes charge of tissue regeneration,” Nature, 529, 307-315, 2016, http://www.nature.com/nature/journal/v529/n7586/full/nature17039.html.
36. SENS Research Foundation, “A Reimagined Research Strategy for Aging. GlycoSENS: Breaking extracellular crosslinks,” accessed June 2017, http://www.sens.org/research/introduction-to-sens-research/extracellular-crosslinks.
37. Ryoji Nagai, David B. Murray, Thomas O. Metz, John W. Baynes, “Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications,” Diabetes, 61(3), 549-559, 2012, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282805/.
38. “In defense of pathogenic proteins,” Science Daily, January 8, 2016, http://www.sciencedaily.com/releases/2016/01/160108083456.htm, based on Juha Saarikangas, Yves Barral, “Protein aggregates are associated with replicative aging without compromising protein quality control,” eLife, 4:e06197, 2015, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635334/.
39. Júlia Santos, Fernanda Leitão-Correia, Maria João Sousa, Cecília Leão, “Dietary Restriction and Nutrient Balance in Aging,” Oxidative Medicine and Cellular Longevity, 2016:4010357, 2016, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670908/.
40. Jim Dryden, “Drastically cutting calories lowers some risk factors for age-related diseases​,” Healthchannel, September 2, 2015, http://www.healthcanal.com/geriatrics-aging/66558-drastically-cutting-calories-lowers-some-risk-factors-for-age-related-diseases%E2%80%8B%E2%80%8B.html, based on Eric Ravussin, Leanne M. Redman, James Rochon, ..., Susan B. Roberts, CALERIE Study Group, “A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity,” Journal of Gerontology: Medical Sciences, 70(9), 1097-1104, 2015, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841173/.
41. Paul W. O’Toole, Ian B. Jeffery, “Gut microbiota and aging,” Science, 350(6265), 1214-1215, 2015, http://science.sciencemag.org/content/350/6265/1214.
42. Ilia Stambler, “Elie Metchnikoff – the founder of longevity science and a founder of modern medicine: In honor of the 170th anniversary,” Advances in Gerontology, 28(2), 207-217, 2015 (Russian) and 5(4), 201-208, 2015 (English), http://www.longevityforall.org/170th-anniversary-of-elie-metchnikoff-the-founder-of-gerontology-may-15-2015/.
43. Anne Brunet, Shelley L. Berger, “Epigenetics of aging and aging-related disease,” Journal of Gerontology: Biological Sciences, 69 Suppl 1, S17-20, 2014, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022130/.
44. Maria Manukyan, Prim B. Singh, “Epigenetic rejuvenation,” Genes to Cells, 17(5), 337-343, 2012, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3444684/.
45. Mitch Leslie, “Researchers rejuvenate aging mice with stem cell genes,” Science, December 15, 2016, http://www.sciencemag.org/news/2016/12/researchers-rejuvenate-aging-mice-stem-cell-genes, based on Alejandro Ocampo, Pradeep Reddy, Paloma Martinez-Redondo, …, Juan Carlos Izpisua Belmonte, "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming," Cell, 167(7), 1719-1733.e12, 2016, http://www.cell.com/fulltext/S0092-8674(16)31664-6.
46. Tarek Baatia, Fanchon Bourassetc, Najla Gharbid, Leila Njimb, Manef Abderrabbae, Abdelhamid Kerkenib, Henri Szwarcd, Fathi Moussa, “The prolongation of the lifespan of rats by repeated oral administration of [60] fullerene,” Biomaterials, 33(19), 4936-4946, 2012,
47. Shawn M. Douglas, Ido Bachelet, George M. Church, “A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads,” Science, 335(6070), 831-834, 2012, http://science.sciencemag.org/content/335/6070/831.
48. John N. Kheir, Laurie A. Scharp, Mark A. Borden, ..., Francis X. McGowan Jr., “Oxygen gas-filled microparticles provide intravenous oxygen delivery,” Science Translational Medicine, 4(140), 140ra88, 2012, https://www.researchgate.net/publication/228089270_Oxygen_Gas-Filled_Microparticles_Provide_Intravenous_Oxygen_Delivery.
49. Ronald Bellamy, Peter Safar, Samuel Tisherman, ..., Harvey Zar, “Suspended animation for delayed resuscitation,” Critical Care Medicine, 24(2Suppl), S24-47, 1996, http://www.ncbi.nlm.nih.gov/pubmed/8608704.
50. Peter Safar, “On the future of reanimatology,” Academic Emergency Medicine, 7(1), 75-89, 2000, http://onlinelibrary.wiley.com/doi/10.1111/j.1553-2712.2000.tb01898.x/abstract.
51. Gennady G. Rogatsky, Avraham Mayevsky, “The life-saving effect of hyperbaric oxygenation during early-phase severe blunt chest injuries,” Undersea Hyperbaric Medicine, 34(2), 75-81, 2007, http://archive.rubicon-foundation.org/xmlui/bitstream/handle/123456789/6468/17520858.pdf?sequence=1.
52. Gennady G. Rogatsky, Edward G. Shifrin, Avraham Mayevsky, “Optimal dosing as a necessary condition for the efficacy of hyperbaric oxygen therapy in acute ischemic stroke: a critical review,” Neurological Research, 25(1), 95-98, 2003, https://www.researchgate.net/publication/10920324_Optimal_dosing_as_a_necessary_condition_for_the_efficacy_of_hyperbaric_oxygen_therapy_in_acute_ischemic_stroke_A_critical_review.
53. Gennady G. Rogatsky, Ilia Stambler, “Hyperbaric oxygenation for resuscitation and therapy of elderly patients with cerebral and cardio-respiratory dysfunction,” Frontiers In Bioscience (Scholar Edition), 9, 230-243, 2017, http://www.bioscience.org/2017/v9s/af/484/2.htm; https://www.bioscience.org/special-issue-details?editor_id=1746.
54. “Paralyzed men move legs with new non-invasive spinal cord stimulation,” NIH News Releases, July 30, 2015, https://www.nih.gov/news-events/news-releases/paralyzed-men-move-legs-new-non-invasive-spinal-cord-stimulation, based on Yury P. Gerasimenko, Daniel C. Lu, Morteza Modaber, …, V. Reggie Edgerton, “Noninvasive Reactivation of Motor Descending Control after Paralysis,” Journal of Neurotrauma, 32(24), 1968-1980, 2015.
55. Marcello Massimini, Fabio Ferrarelli, Steve K. Esser, Brady A. Riedner, Reto Huber, Michael Murphy, Michael J. Peterson, Giulio Tononi, “Triggering sleep slow waves by transcranial magnetic stimulation,” Proceedings of the National Academy of Sciences USA, 104(20), 8496-8501, 2007, http://www.pnas.org/content/104/20/8496.full.
56. Max Schaldach, Electrotherapy of the Heart: Technical Aspects in Cardiac Pacing, Springer-Verlag, Berlin, 2012.
57. David Blokh, Ilia Stambler, “Information theoretical analysis of aging as a risk factor for heart disease,” Aging and Disease, 6, 196-207, 2015, http://www.aginganddisease.org/EN/10.14336/AD.2014.0623.
58. David Blokh, Ilia Stambler, “The application of information theory for the research of aging and aging-related diseases,” Progress in Neurobiology, S0301-0082(15)30059-9, 2016, doi: http://dx.doi.org/10.1016/j.pneurobio.2016.03.005.
59. Alexey Moskalev, Elizaveta Chernyagina, Vasily Tsvetkov, Alexander Fedintsev, Mikhail Shaposhnikov, Vyacheslav Krut'ko, Alex Zhavoronkov, Brian K. Kennedy, “Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic,” Aging Cell, 15(3), 407-415, 2016, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854916/.
60. Georg Fuellen, Paul Schofield, Thomas Flatt, ..., Andreas Simm, “Living Long and Well: Prospects for a Personalized Approach to the Medicine of Ageing,” Gerontology, 62(4), 409-416, 2016.
61. Robert N. Butler, Richard Sprott, Huber Warner, Jeffrey Bland, Richie Feuers, Michael Forster, Howard Fillit, S. Mitchell Harman, Michael Hewitt, Mark Hyman, Kathleen Johnson, Evan Kligman, Gerald McClearn, James Nelson, Arlan Richardson, William Sonntag, Richard Weindruch, Norman Wolf, “Biomarkers of aging: from primitive organisms to humans,” Journal of Gerontology. A. Biological Sciences Medical Sciences, 59, B560-567, 2004.
62. Thomas Craig, Chris Smelick, Robi Tacutu, Daniel Wuttke, ..., João Pedro de Magalhães, “The Digital Ageing Atlas: integrating the diversity of age-related changes into a unified resource,” Nucleic Acids Research, 43, D873-878, 2015, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384002/.
63. David Blokh, Ilia Stambler, “The use of information theory for the evaluation of biomarkers of aging and physiological age,” Mechanisms of Ageing and Development, 163, 23-29, 2017, doi: http://dx.doi.org/10.1016/j.mad.2017.01.003.
64. Alexander Zhavoronkov, Bhupinder Bhullar, “Classifying aging as a disease in the context of ICD-11,” Frontiers in Genetics, 6, 326, http://journal.frontiersin.org/article/10.3389/fgene.2015.00326/full.
65. Ilia Stambler, “Degenerative Aging as a Medical Condition,” Longevity for All, January 1, 2016, 
http://www.longevityforall.org/degenerative-aging-as-a-medical-condition/;
Ilia Stambler, “Recognizing degenerative aging as a treatable medical condition: methodology and policy,” Aging and Disease, 8(5), 2017, http://www.aginganddisease.org/EN/10.14336/AD.2017.0130;
Ilia Stambler, “Human life extension: opportunities, challenges, and implications for public health policy,” in Alexander Vaiserman (Ed.), Anti-aging Drugs: From Basic Research to Clinical Practice, Royal Society of Chemistry, London, 2017, pp. 535-564.

Books


Longevity Promotion: Multidisciplinary Perspectives


A History of Life-Extensionism in the Twentieth Century

Articles

Longevity Advocacy

The Tasks of Longevity Promotion: Science, Ethics and Public Policy - Potential presentation topics on longevity research

Position Paper: The Critical Need to Promote Research of Aging. Aging and Disease, 2015

The pursuit of longevity - The bringer of peace to the Middle East. Current Aging Science, 6, 25-31, 2014

Recognizing degenerative aging as a treatable medical condition: methodology and policy. Aging and Disease, 2017

Frequently Asked Questions on the Ethics of Lifespan and Healthspan Extension

Longevity Science

The application of information theory for the research of aging and aging-related diseases. Progress in Neurobiology, 2016

The use of information theory for the evaluation of biomarkers of aging and physiological age. Mechanisms of Ageing and Development, 2017

Hyperbaric oxygenation for resuscitation and therapy of elderly patients with cerebral and cardio-respiratory dysfunction. Frontiers In Bioscience, 2017

Estimation of Heterogeneity in Diagnostic Parameters of Age-related Diseases. Aging and Disease, 5, 218-225, 2014.

Information theoretical analysis of aging as a risk factor for heart disease. Aging and Disease, 6, 196-207, 2015

Applying information theory analysis for the solution of biomedical data processing problems. American Journal of Bioinformatics, 3 (1), 17-29, 2015

Stop Aging Disease! ICAD 2014. Aging and Disease, 6 (2), 76-94, 2015

The Historical Evolution of Evolutionary Theories of Aging

Potential Interventions to Ameliorate Degenerative Aging

Longevity History

Introduction to "A History of Life-Extensionism in the Twentieth Century"

Life-extensionism as a pursuit of constancy

Has aging ever been considered healthy? Frontiers in Genetics. Genetics of Aging, 6, 00202, 2015

The Legacy of Elie Metchnikoff

Longevity and the Jewish Tradition

Longevity and the Indian Tradition

Longevity in the Ancient Middle East and the Islamic Tradition

Longevity and the Christian Tradition

Life extension - a conservative enterprise? Some fin-de-siecle and early twentieth-century precursors of transhumanism. Journal of Evolution and Technology, 21, 13-26, 2010

The unexpected outcomes of anti-aging, rejuvenation and life extension studies: an origin of modern therapies. Rejuvenation Research, 17, 297-305, 2014

Heroism and Heroic Death in Nineteenth Century Literature

Reductionism and Holism in the History of Aging and Longevity Research: Does the Whole have Parts?

Aristotle on Life and Long Life