Will Geroprotectors Extend Lifespan to 150+ Years?

By now, just about everyone knows that geroprotectors and other life extension treatments (LETs) can extend the lifespans of model organisms such as mice. Examples include metformin [1, 2], rapamycin [3, 4], calorie restriction [5, 6], resveratrol [7, 8], and NAD+ precursors [9, 10]. The number of PubMed publications and Google searches has been increasing exponentially for many specific LETs.

What many may not know, though, is that there aren’t just a handful of these LETs. There are actually thousands of LETs that have emerged over the last hundred years, which is around the time that life extension in mice was first discovered [11]. And between 1950 and 2000, hundreds of diets, molecules, exercises, and other interesting methods, were discovered to extend mouse lifespan.

For some odd reason, it took a long time for the public and our healthcare system to become aware of all of this [12-20]. Although the topic is now popular, not one time did I learn about extending organism lifespan or reversing aging during the time I spent as a biomedical undergrad.

That changed my last semester, when I watched some YouTube videos of Dr. Aubrey de Grey, Ray Kurzweil, and Dr. Martine Rothblatt [21-23]. After watching the videos, I asked my colleagues and professors about the topic. Somehow, not a single one of them had heard of this seemingly promising research. Not even the gerontology department had heard of it.

I hope one day to discover the reasons behind this historical lack of awareness. But, for now, there's no time. The research must be developed!

Brief History of Life Extension Research

It was not until around the beginning of the 21st century that we began to see genetic edits extending the lifespan of model organisms [24-30]. One life extension gene edit after another was discovered as the years went by.

Before we knew it, hundreds of different genetic edits had extended mouse lifespans. Hundreds more had extended the lifespans of other model organisms. And their health-spans were dramatically increased also.

Single genes were deleted or over-expressed to extend the lives of mice by up to 50% [31-35]. Diets [36, 37], small molecules [38, 39], and other interesting approaches [40, 41] were discovered. And adult stem cells extended mouse lifespan between 10% and 35% [42].

Recently, Dr. Nir Barzilai began planning a human clinical trial (TAME) using metformin to target age-related diseases [43]. It could be one of the greatest trials ever conducted. Metformin won't necessarily extend human lifespan exactly as we’ve observed in model organisms [1, 2]. But this may trigger an avalanche of new research by massive biotech companies with the goal to help us live healthy lives up to 150 years or longer.

Direction of Life Extension Research Today

Imagine an industry in which thousands of diets, drugs, supplements, genetic edits, and stem cells are tested and combined for optimal healthy life extension. It could be as simple as a quick injection for gene therapy. Or maybe we could consume a combination of strawberries and green tea for the fisetin [44] and EGCG [45]. This is the direction that LETs are going.

Only a few scientists have been bold enough to combine multiple LETs in tests on model organisms [46, 47]. In 2019, Dr. George Church and his research team published a spectacular paper. It described the results of making three genetic edits with a single gene therapy combination in mice [48].

Dr. Church didn't take time to measure life extension in the mice because he thinks that measuring life extension in humans will take too long. Imagine a forty year trial! To prove life extension in humans, we would have to live far longer than 120 years. Instead, Dr. Church believes we must focus on preventing and reversing parameters of biological aging because we can measure them faster.

So he and his team targeted four age-related diseases in mice. It wasn’t too surprising that their health-span increased. And their biological aging process slowed compared to controls. In other words, the mice remained youthful for much longer.

And why would he stop there? His plan is to test a combo treatment of gene therapies in dogs. It will contain not three, not four, but over forty of promising gene therapies [49].

Speculating on the Potential of Life Extension

In yeast, flies, and nematodes, single LETs can extend lifespan well over 100% [50, 51]. And many single LETs can extend mouse lifespan by 20% to 40%.

Let's do some speculative math. Assume we observe in mice at least a 10% increase in maximum lifespan from each of 45 gene therapies. 45 times 10% equals a 450% increase in lifespan.

If that translated over to humans, we would live longer than 400 years. And we may even be healthier than today’s healthiest 25-year-olds.

However, some studies have indicated that combinations aren't synergistic. For example, if two treatments extend mouse lifespan by 10% each on their own, we might observe an increase of about 15% from the combination.

So, backing off, imagine a 200% life extension in humans from something as simple as just drinking enough green tea, injecting a few stem cells, and applying some gene therapies. Should we believe this is possible?

Are humans too complex? Do humans live too long? Well, mice are much more complex and live much longer than nematodes. And we have observed 20% increases in mouse lifespan from treatments that only extend nematode lifespan by 10% [52, 53].

So the complexity argument doesn’t always work. And, at the end of the day, we might as well check how thousands of model organism studies translate over to humans. Let's not rule out possibilities until we've properly tested them. We should conduct more human trials like TAME, but with combinations of LETs.

Lifespans of 150 years would be less than a 50% increase in maximum lifespan for humans. Maybe it will only take a few LETs to help us all get there. And there are hundreds of promising LETs to explore.

Audacious Hope

Why only 150 years? Have we already discovered a method to keep people alive, as some enthusiasts describe it, "long enough to live forever"? In other words, do we already have the tools we need to survive just long enough to make better tools, over and again, and achieve longevity escape velocity?

We spend trillions of dollars targeting symptoms of specific diseases. But, right in front of our face, we might already have a relatively inexpensive method to achieve what our ancestors have hoped for millennia. Maybe we can finally, once and for all, put an end to suffering and death from aging!

References

1. Martin-Montalvo A. et al. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4:2192 doi: 10.1038/3192 (2013).
2. Anisimov VN, Berstein LM, Egormin PA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008;7:2769–2773.
3. Miller RA, Harrison DE, Astle CM, et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13(3):468‐477. doi:10.1111/acel.12194
4. Stacey RS et al. (2013) TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metalbolism. 15(5): 713–724.
5. Weindruch R, Walford RL (1988) The retardation of aging and disease by dietary restriction. Charles C Thomas, Springfield.
6. Su-Ju Lin, et al. (2004) Calorie restriction extends yeast life span by lowering the level of NADH. Genes & Development. 18(1): 12–16.
7. Strong, R. et al. Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 68, 6–16.
8. Liu T et al (2015) Resveratrol attenuates oxidative stress and extends life span in the annual fish Nothobranchius guentheri. Rejuvenation Res 18:225–233.
9. Hongbo Zhang et al. (2016) NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. Vol. 352, Issue 6292, pp. 1436-1443.
10. Vitaly Balan et al. (2008) Life Span Extension and Neuronal Cell Protection by Drosophila Nicotinamidase. Journal of Biological Chemistry. 283(41):27810-27819.
11. McCay C. M. et al. (1935) The effect of Retarded Growth Upon the Length of Life Span and Upon the Ultimate Body Size: One Figure. The Journal of Nutrition. 10(1): 63-79.
12. De Marte ML and Enesco HE (1986) Influence of Low Tryptophan Diet on Survival and Organ Growth in Mice. Mechanisms Ageing Development. 36(2):161-71.
13. Massie HR and Aiello VR (1984) The Effect of Dietary Methionine on the Copper Content of Tissues and Survival of Young and Old Mice. Experimental Gerontology. 19(6):393-9.
14. Miller DS and Payne PR (1968) Longevity and protein intake. Experimental Gerontology. 3(3): 231-232.
15. Knoll J (1988) The Striatal Dopamine Dependency of Life Span in Male Rats. Longevity Study With (-)Deprenyl. Mechanisms Ageing Development. 46(1-3):237-62.
16. Comfort, A., Youhotsky-Gore, I., and Pathmanathan, K. (1971). "Effect of ethoxyquin on the longevity of C3H mice." Nature 229(5282):254-255.
17. Dilman, VM et al. (1979) Increase in lifespan of rats following polypeptide pineal extract treatment.
18. Clapp NK et al. (1979) Effects of the Antioxidant Butylated Hydroxytoluene (BHT) on Mortality in BALB/c Mice. Gerontology. 34(4):497-501.
19. Holloszy JO et al. (1985) Effect of Voluntary Exercise on Longevity of Rats. Applied Physiology. 59(3):826-31.
20. Walter P and William R (1994) Pineal control of aging: Effect of melatonin and pineal grafting on aging mice. PNAS. 91: 787-791.
21. TED. A roadmap to end aging | Aubrey de Grey. YouTube. TED. Jan 16, 2007. 23:26. https://www.youtube.com/watch?v=8iYpxRXlboQ.
22. TED. The accelerating power of technology | Ray Kurzweil. YouTube. TED. Jan 12, 2007. 23:26. https://www.youtube.com/watch?v=IfbOyw3CT6A.
23. TED. Martine Rothblatt: My daughter, my wife, our robot, and the quest for immortality. YouTube. TED. May 18, 2015. 21:04. https://www.youtube.com/watch?v=rTJpJlVkRTA.
24. Wesley WB and Chester HC (2000) Myocardial Fibrosis in Transforming Growth Factor β1Heterozygous Mice. Journal of Molecular and Cellular Cardiology. 32(2): 187-195.
25. Xiaoping Y et al. Metallothionein Prolongs Survival and Antagonizes Senescence-Associated Cardiomyocyte Diastolic Dysfunction: Role of Oxidative Stress. FASEB J. 20(7):1024-6.
26. Chih-Hsien Chiu et al. (2004) Effect of a C/EBP gene replacement on mitochondrial biogenesis in fat cells. Genes Development.18(16): 1970-1975.
27. Miskin et al. (1999) "AlphaMUPA mice: a transgenic model for increased life span." Neurobiol. Aging 20(5):555-564.
28. Coschigano KT et al. (2000) Assessment of Growth Parameters and Life Span of GHR/BP Gene-Disrupted Mice. Endocrinology. 41(7):2608-13.
29. Matthias B et al. (2003) Extended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue. Science. 299(5606):572-4.
30. Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, and Roth GS. Extending the lifespan of long-lived mice. Nature 414: 412, 2001.
31. Benigni et al. (2009) "Disruption of the Ang II type 1 receptor promotes longevity in mice." J. Clin. Invest. 119(3):524-530.
32. De Luca, G., Ventura, I., Sanghez, V., Russo, M. T., Ajmone-Cat, M. A., Cacci, E., Martire, A., Popoli, P., Falcone, G., Michelini, F., et al. (2013). "Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1." Aging Cell 12(4):695-705.
33. Allon Canaan et al. (2014) Extended lifespan and reduced adiposity in mice lacking the FAT10 gene. PNAS. 111 (14) 5313-5318.
34. Camille de Lombares et al. (2019) Dlx5 and Dlx6 Expression in GABAergic Neurons Controls Behavior, Metabolism, Healthy Aging and Lifespan. Aging. 11(17):6638-6656.
35. Longevity and age-related pathology of mice deficient in pregnancy-associated plasma protein-A.
36. Samantha MS et al. (2019) Branched-chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control. Nature Metabolism. 1, 532-545.
37. Xiang-Yong Li et al. (2018) Identification of a Sustainable Two-Plant Diet That Effectively Prevents Age-Related Metabolic Syndrome and Extends Lifespan in Aged Mice. Nutritional Biochemistry. 51:16-26.
38. Nidia Basso et al. (2007) Protective effect of long-term angiotensin II inhibition. Am J Physiol Heart Circ Physiol. 293(3):H1351-8.
39. Yao Dang et al. (2019) Berberine ameliorates cellular senescence and extends the lifespan of mice via regulating p16 and cyclin protein expression. Aging Cell. 19(1).
40. Dajeong Kim et al. (2015) Health Span‐Extending Activity of Human Amniotic Membrane‐ and Adipose Tissue‐Derived Stem Cells in F344 Rats. Stem Cells Journal. 4(10).
41. Tracy LH et al. (2019) Extension of longevity and reduction of inflammation is ovarian-dependent, but germ cell-independent in post-reproductive female mice. Geroscience. 41(1):25-38.
42. Alexey VK et al. (2015) Informational Theory of Aging: The Life Extension Method Based on the Bone Marrow Transplantation. Hindawi. 14.
43. Barzilai N et al. (2018) Metformin as a Tool to Target Aging. Cell Metabolism. 23(6): 1060-1065.
44. Matthew JY et al. (2018) Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 36: 18-28.
45. Yucun Niu et al. (2013) The phytochemical, EGCG, extends lifespan by reducing liver and kidney function damage and improving age-associated inflammation and oxidative stress in healthy rats. Aging Cell. 12(6).
46. Pearson, K. J., Baur, J. A., Lewis, K. N., Peshkin, L., Price, N. L., Labinskyy, N., Swindell, W. R., Kamara, D., Minor, R. K., Perez, E., Jamieson, H. A., Zhang, Y., Dunn, S. R., Sharma, K., Pleshko, N., Woollett, L. A., Csiszar, A., Ikeno, Y., Le Couteur, D., Elliott, P. J., Becker, K. G., Navas, P., Ingram, D. K., Wolf, N. S., Ungvari, Z., Sinclair,D.A.,anddeCabo,R.(2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan. Cell Metab. 8, 157-168.
47. Ming Xu et al. (2018) Senolytics Improve Physical Function and Increase Lifespan in Old Age. Nature Medicine. 24(8):1246-1256.
48. Noah Davidsohn et al. (2019) A single combination gene therapy treats multiple age-related diseases. PNAS. 116 (47) 23505-23511.
49. https://www.rejuvenatebio.com/.
50. Kaushik et al. (2015) "Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart." Sci Transl Med 7(292):292ra99.
51. Pathak P, et al. (2016) Rasayana effect of Guduchi Churna on the life span of Drosophila melanogaster Ayu.
52. Gallant S et al. (1999) Carnosine as a potential Anti-senescence Drug. Biochemistry (Moscow). 63(7): 866-868.
53. Edwards, C et al. (2015) Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans. BMC Genet. 16: 8.