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The War on Aging: An Update from the Front Lines

Original Article: The War on Aging: An Update from the Front Lines

 

 

great-war-1

 

Interventions into the degenerative aging process are still only in their infancy. A long war will need to be fought from basic research on cell cultures and animal models to deliver, eventually, effective, safe and widely available human anti-aging therapies.

Currently promising research is progressing, especially as regards potential pharmaceutical interventions into the aging process. [1] [2] [3]

Below are some examples.

1. On November 28, 2015, the FDA approved the testing of Metformin, a decades-old anti-diabetic (blood sugar reducing) medication, as the first drug to treat degenerative aging, rather than particular diseases, due to its capacity to reduce cancers and other morbidities.[4]

2. On November 25, 2015, the FDA approved an adjuvant therapy (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.[5]

3. The immunosuppressant drug Rapamycin, believed to mimic the healthspan extending effects of calorie restriction (CR-mimetic), has produced 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.[6]

4. By splicing the circulatory systems of animals (mice) together, via the process of “parabiosis”, young blood was shown to have rejuvenating effects on old tissues, including the heart, brain, and muscle tissues, with improved strength and cognitive ability. Some of the implicated rejuvenating substances 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.[7]

5. 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.[8] 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.[9] Senescent cells can also be eliminated by immunological means, such as vaccines, antibodies and killer T cells.[10]

6. 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 enzyme[11] important for enhanced stress response, cardiovascular protection, improved cognitive function and synaptic plasticity, and suppressing inflammation.[12] 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).[13]

7. 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 process and derivative pathologies, such as cancer.[14]

8. 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.[15] 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.[16] Yet, very 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).[17]

9. 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)[18] and even pharmaceutical treatments (e.g.  using the Human Growth or FGF21 hormone).[19] [46]

10. 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.[20] [21] [22]

11. 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).[23] 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.[24] 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.[25]

12. Anti-inflammatory medications have been widely tested to diminish aging-related degenerative pathologies, such as neuro-degenerative pathologies, and to extend healthy lifespan in animal models.[26] But also pro-inflammatory effects have been shown to be important for tissue regeneration.[27]

13. 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 (e.g. 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.[28] 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.[29] Removing too much of them and in wrong places may do more damage than good.

14. 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).[30] But what is “the balance”? How much is “too much” or “too little”? The guiding rule is always “The dose makes the poison”.[3] 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.[31] Also new ways are being sought to enrich the “microbiome” (intestinal bacteria populations) for healthy longevity[32], for example using probiotic diets – the idea that goes back to the origins of scientific aging research, over a century ago.[33]

15. 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 interfereing RNAs (siRNAs) and micronutrients as potential therapeutic agents.[34]

16. Interventions into degenerative aging are now beginning to reach the “nano” level. Some of the uses of nanomedicine against degenerative aging include nanoparticles, such as Buckminsterfullerene or “bucky-balls” C60 with assumed antiviral, antioxidant, anti-amyloid, immune stimulating and other therapeutic activities, and some reported lifespan extending results in animal models.[35] 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.[36] [37] 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.[38]

17. Anti-aging and life-extending interventions do not necessarily need to be chemical or biological, but can also be physical, in particular as relates to various resuscitation technologies (hypothermia and suspended animation,[39] oxygenation,[40] electromagnetic stimulation[41]). 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. 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.[42] 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”.[43] 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.[44] [45]

 

Acknowledgment

I thank Steve Hill and Kevin Perrott for their suggestions regarding the diversity of research areas.

 

References

[1] Jin K, Simpkins JW, Ji X, Leis M, Stambler I. 2015. 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, 1-5http://www.aginganddisease.org/EN/10.14336/AD.2014.1210

[2] Stambler I. 2015. Stop Aging Disease! ICAD 2014. Aging and Disease 6 (2), 76-94http://www.aginganddisease.org/EN/10.14336/AD.2015.0115

[3] Stambler I. 2014. A History of Life-Extensionism in the Twentieth Century, Longevity History. http://www.longevityhistory.com/

[4] Macdonald F. December 1, 2015. A common diabetes drug will be trialled as an anti-ageing elixir from next year. Research suggests it could help people live to 120. Science Alert

http://www.sciencealert.com/a-common-diabetes-drug-will-be-trialled-as-an-anti-ageing-elixir-from-next-year

[5] Preidt R. November 25, 2015. 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.

http://www.webmd.com/cold-and-flu/news/20151125/fda-approves-first-flu-shot-with-added-ingredient-to-boost-immune-response

[6] Richardson A, Galvan V, Linc AL, Oddo S. 2015. How longevity research can lead to therapies for Alzheimer’s disease: The rapamycin story. Experimental Gerontology. 68, 51–58http://www.sciencedirect.com/science/article/pii/S0531556514003490

[7] Scudellari M. 21 January 2015. Ageing research: Blood to blood. Nature 517 (7535).http://www.nature.com/news/ageing-research-blood-to-blood-1.16762

[8] Wadenov N. November 2, 2011. Purging Cells in Mice Is Found to Combat Aging Ills. New York Times. Based on Darren J. Baker, …, Jan M. van Deursen. 2011, Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479(7372), 232-236.

http://www.nytimes.com/2011/11/03/science/senescent-cells-hasten-aging-but-can-be-purged-mouse-study-suggests.html?_r=0

[9] Yi Zhu et al. 2015. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658.  http://onlinelibrary.wiley.com/doi/10.1111/acel.12344/abstract

[10] Sagiv A, Krizhanovsky V. 2013. Immunosurveillance of senescent cells: the bright side of the senescence program. Biogerontology 14 (6), 617-628 http://link.springer.com/article/10.1007/s10522-013-9473-0

[11] Ledford H. 22 February 2012. Sirtuin protein linked to longevity in mammals. Male mice overproducing the protein sirtuin 6 have an extended lifespan. Nature News. Based on Yariv Kanfi, …, Haim Y. Cohen. 08 March 2012. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221. http://www.nature.com/news/sirtuin-protein-linked-to-longevity-in-mammals-1.10074

[12] Maheedhar Kodali, Vipan K. Parihar, Bharathi Hattiangady, Vikas Mishra, Bing Shuai & Ashok K. Shetty. 2015. Resveratrol Prevents Age-Related Memory and Mood Dysfunction with Increased Hippocampal Neurogenesis and Microvasculature, and Reduced Glial Activation. Scientific Reports 5, 8075http://www.nature.com/articles/srep08075

[13] Weintraub K. February 3, 2015. The Anti-Aging Pill. MIT Technology Review.http://www.technologyreview.com/news/534636/the-anti-aging-pill/

[14] Ian F Robey and Natasha K Martin. 2011. Bicarbonate and dichloroacetate: Evaluating pH altering therapies in a mouse model for metastatic breast cancer. BMC Cancer 11, 235http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125283/

[15] Jennifer L. Olson, Anthony Atala, and James J. Yoo. 2011. Tissue Engineering: Current Strategies and Future Directions. Chonnam Med J. 47(1), 1–13 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214857/

[16] Giuseppe Orlando, Shay Soker, Robert J. Stratta, and Anthony Atala. 2013. Will Regenerative Medicine Replace Transplantation? Cold Spring Harb Perspect Med.  3(8), a015693http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214857/

[17] New drug triggers tissue regeneration: Faster regrowth and healing of damaged tissues. Science Daily. June 11, 2015. Based on Yongyou Zhang, et al. 2015 June 12. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science 348(6240), aaa2340http://www.sciencedaily.com/releases/2015/06/150611144438.htm

[18] Living organ regenerated for first time: Thymus rebuilt in mice. Science Daily. April 8, 2014. Based on N. Bredenkamp N., Nowell C. S., Blackburn C. C. 2014. Regeneration of the aged thymus by a single transcription factor. Development 141 (8), 1627 http://www.sciencedaily.com/releases/2014/04/140408115610.htm

[19] Life-extending hormone bolsters the body’s immune function. Science Daily. January 12, 2016. Based on Yun-Hee Youm, Tamas L. Horvath, David J. Mangelsdorf, Steven A. Kliewer, Vishwa Deep Dixit. 2016. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proceedings of the National Academy of Sciences, 201514511 http://www.sciencedaily.com/releases/2016/01/160112093545.htm

[20] Mariela Jaskelioff, …, Ronald A. DePinho. January 6, 2011, first published online on November 28, 2010. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature, 469, 102-106. Reported in Ian Sample, November 28, 2010. Harvard scientists reverse the ageing process in mice – now for humans, Guardian  http://www.guardian.co.uk/science/2010/nov/28/scientists-reverse-ageing-mice-humans

[21] Bär C and Blasco MA. 2016. Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases. F1000Research 2016, 5 (F1000 Faculty Rev):89 (doi:10.12688/f1000research.7020.1)http://f1000research.com/articles/5-89/v1

[22] Erez Eitan, …, Esther Priel. 2012. Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis. EMBO Mol Med. 4(4), 313-329http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376858/

[23] Skulachev VP, et al. 2009. An attempt to prevent senescence: a mitochondrial approach. Biochimica et Biophysica Acta, 1787(5), 437-61 http://www.sciencedirect.com/science/article/pii/S0005272808007573

[24] Bender E. September 22, 2015. Stopping free radicals at their source. Novartis Institute for Biomedical Research. Based on Adam L. Orr et al. 2015. Suppressors of superoxide production from mitochondrial complex III. Nature Chemical Biology 11(11), 834-836 https://www.nibr.com/stories/discovery/stopping-free-radicals-their-source

[25] Eric A. Schon and Salvatore DiMauro. 2003. Medicinal and Genetic Approaches to the Treatment of Mitochondrial Disease. Current Medicinal Chemistry, 10, 2523-2533http://homepages.ihug.co.nz/~Smconnell/Medicinal%20and%20Genetic%20Approaches%20to%20Mitochonrial%20Disease.pdf

[26] Could ibuprofen be an anti-aging medicine? Buck Institute. December 11, 2014. Based on Chong He, et al. 2014. Enhanced Longevity by Ibuprofen, Conserved in Multiple Species, Occurs in Yeast through Inhibition of Tryptophan Import. PLoS Genet 10(12): e1004860 http://www.buckinstitute.org/buck-news/could-ibuprofen-be-an-anti-aging-medicine

[27] Michael Karin and Hans Clevers. 21 January 2016. Reparative inflammation takes charge of tissue regeneration. Nature 529, 307–315 http://www.nature.com/nature/journal/v529/n7586/full/nature17039.html

[28] SENS Research Foundation. A Reimagined Research Strategy for Aging. GlycoSENS: Breaking extracellular crosslinks http://www.sens.org/research/introduction-to-sens-research/extracellular-crosslinks

[29] In defense of pathogenic proteins. January 8, 2016. Science Daily. Based on Juha Saarikangas, Yves Barral. 2015. Protein aggregates are associated with replicative aging without compromising protein quality control. eLife, 2015;4 http://www.sciencedaily.com/releases/2016/01/160108083456.htm

[30] Santos J, Leitão-Correia F, Sousa MJ, Leão C. 2016. Dietary Restriction and Nutrient Balance in Aging. Oxid Med Cell Longev. 2016:4010357 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670908/

[31] Dryden J. September 2, 2015. Drastically cutting calories lowers some risk factors for age-related diseases​​. Healthchannel. Based on Ravussin E, et al. September 2015. 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 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

[32] O’Toole PW, Jeffery IB. 2015. Gut microbiota and aging. Science. 350(6265), 1214-1215http://science.sciencemag.org/content/350/6265/1214

[33] Ilia Stambler. 2015. 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 (English). http://www.longevityhistory.com/articles/ab15.php

[34] Brunet A, Berger SL. 2014. Epigenetics of aging and aging-related disease. J Gerontol A Biol Sci Med Sci. 69 Suppl 1:S17-20 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022130/

[35] Tarek Baati, …, Fathi Moussa. 2012. The prolongation of the lifespan of rats by repeated oral administration of [60] fullerene. Biomaterials, 33(19), 4936-4946http://www.sciencedirect.com/science/article/pii/S0142961212003237

[36] Shawn M. Douglas, Ido Bachelet, George M. Church. 17 February 2012. A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads. Science, 335 (6070), 831-834http://science.sciencemag.org/content/335/6070/831

[37] Griffiths S. 18 March 2015. Nanorobots trial to begin in humans: Microscopic DNA devices could be injected into a leukaemia patient in a bid to destroy abnormal cells. Daily Mailhttp://www.dailymail.co.uk/sciencetech/article-3000904/Nanorobots-trial-begin-humans-Microscopic-DNA-devices-injected-leukaemia-patient-bid-destroy-abnormal-cells.html

[38] Kheir JN, et al. 2012 June 27. Oxygen gas-filled microparticles provide intravenous oxygen delivery. Science Translational Medicine, 4(140):140ra88 https://www.researchgate.net/publication/228089270_Oxygen_Gas-Filled_Microparticles_Provide_Intravenous_Oxygen_Delivery

[39] Bellamy R, et al. 1996. Suspended animation for delayed resuscitation. Critical Care Medicine. 24(2 Suppl):S24-47 http://www.ncbi.nlm.nih.gov/pubmed/8608704

[40] Rogatsky GG, Mayevsky A. 2007. The life-saving effect of hyperbaric oxygenation during early-phase severe blunt chest injuries. Undersea Hyperbaric Medicine 34(2), 75-81 http://archive.rubicon-foundation.org/xmlui/bitstream/handle/123456789/6468/17520858.pdf?sequence=1

[41] NIH/National Institute of Biomedical Imaging and Bioengineering. July 30, 2015. Paralyzed men move legs with new non-invasive spinal cord stimulation. Based on Gerasimenko Yury P., et al. December 2015. Noninvasive Reactivation of Motor Descending Control after Paralysis. Journal of Neurotrauma. 32(24), 1968-1980http://www.eurekalert.org/pub_releases/2015-07/niob-pmm073015.php

[42] Blokh D and Stambler I. 2015. Information theoretical analysis of aging as a risk factor for heart disease. Aging and Disease, 6 (3), 196-207 http://www.aginganddisease.org/EN/10.14336/AD.2014.0623

[43] Georg Fuellen, et al. December 17, 2015. Living Long and Well: Prospects for a Personalized Approach to the Medicine of Ageing. Gerontologyhttps://www.researchgate.net/publication/287212601_Living_Long_and_Well_Prospects_for_a_Personalized_Approach_to_the_Medicine_of_Ageing

[44] Zhavoronkov A and Bhullar B. 2015. Classifying aging as a disease in the context of ICD-11. Frontiers in Genetics 6, 326. doi: 10.3389/fgene.2015.00326http://journal.frontiersin.org/article/10.3389/fgene.2015.00326/full

[45] Stambler I. January 1, 2016. Recognizing Degenerative Aging as a Treatable Medical Condition – Policy and Methodology. Longevity for All http://www.longevityforall.org/recognizing-degenerative-aging-as-a-treatable-medical-condition-policy-and-methodology/

[46] Fahy G. 2003. Apparent induction of partial thymic regeneration in a normal human subject: a case report., J Anti Aging Med. 2003;6(3):219-27. http://www.ncbi.nlm.nih.gov/pubmed/14987435

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Dr. Ilia Stambler is the Outreach Coordinator for the International Society on Aging and Disease (ISOAD)

http://isoad.org/

Image: Diorama of Great War front with sectioned field dressing station English 1960-1975
This file comes from Wellcome Images, a website operated by Wellcome Trust, a global charitable foundation based in the United Kingdom. Refer to Wellcome blog post

Library reference: Science Museum A602834.A602834 Pt1.SRGC100098

Photo number: L0057926

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