Have we moved past calorie restriction, yet?
In the quest for a longer, healthier life, it might appear no stone has been left unturned. But unfortunately that is an illusion.
Back in the 1930s Clive Mckay discovered that calorie restriction extended the lifespan of rats by about a third (1). And that remained the benchmark.
Cynthia Kenyon did a series of experiments in the C. elegans worm model and discovered various insulin/IG-F related pathways that extended lifespan considerably (2), but it wasn’t until around 2009 that the first pharmaceutical approach - using rapamycin - was able to extend rodent lifespan to a comparable extent to CR (3). This was a remarkable discovery, and showed that lifespan benefits did not require lifelong dosing - certainly useful for elderly humans - but nevertheless did not constitute an independent anti-aging pathway, as mTOR is intimately tied into the calorie sensing network.
Very recently it has been shown that dosing with Glycine and NAC (N-acetyl-cysteine), extends lifespan in mice by a significant degree (~24%) and also has clear health benefits in older humans (4)(5). This has triggered the predictable response from certain quarters that the ROS (Reactive Oxygen Species) theory of aging is alive and well, due to the critical contribution of glycine and cysteine to intracellular glutathione. Once again however, this intervention is working via the insulin/mTOR pathway and is not an independent mechanism. Why?
The work of Wulf Droge long argued that cysteine supplementation could restore the set point of the insulin receptor - known to be sensitive to ROS, even in the fasted state - and restore autophagy(6), which is prophetic given the recent GlyNAC trials. This ties the ROS theory of aging into Blagosklonny’s hyperfunction theory (7), suggesting that persistent growth signaling drives hyperfunction of mitochondria and a consequent rise in ROS that disables autophagy, leading to a positive (but bad!) feedback loop in the elderly. Though the papers do not state it (4)(5), the truth is that the GlyNAC trials show that decreasing ROS is really turning down growth signaling by restoring the fasted sensitivity of the insulin receptor.
Fibroblasts obtained from old humans were found in 2015 to have an epigenetically silenced SHMT2 (serine hydroxymethyltransferase) mitochondrial gene, which disables the conversion of serine to glycine within mitochondria and downstream, mitochondrial translation - effectively blocking new mitochondria from being made (8). But this was partially compensated for by the addition of glycine. Therefore the GlyNAC intervention also permits the re-establishing of normal, controlled mitochondrial growth.
Could this mitochondrial dysfunction be the intracellular equivalent of diabetes type II, where cells try and save themselves from excessive plasma glucose, but in this case results in a blockade on mitochondrial biogenesis in order to prevent ROS induced senescence?
Therefore aging can be viewed as a cellular response to excessive growth signaling - basically a diabetes type II problem - rather than a cellular damage problem, which is more akin to diabetes type I.
If this is true, then various efforts to remove permanently damaged senescent cells (9)(10) are misdiagnosing the illness, by trying to treat the equivalent of diabetes type I when the patient is suffering from diabetes type II. This is treating the symptom, not the disease, and is likely to merely to compress late life mortality (11).
Moving from cellular removal to cellular replacement, telomerase gene therapy has successfully extended mouse life span (12), which like senolytics appear on the face of it to challenge the assertion of this paper that lifespan extension is always achieved via inhibition of growth signaling. Yet side stepping the need for gene therapy and engineering mice to be born with hyper-long telomeres (13), revealed startling metabolic benefits reminiscent of calorie restriction.
Therefore it is predicted that both telomere shortening and ROS will be eventually shown to feed into senescence via the mTOR pathway.
Finally, plasma exchange experiments have caused considerable excitement in life extension circles (14), (though they are yet to demonstrate meaningful lifespan extension). Yet what could be more like calorie restriction than removing the plasma of the old and replacing it with saline and albumin (or the plasma of the young)?
We must conclude that ALL successful lifespan extension studies to date involve the insulin receptor/mTOR complex to some significant degree, and that no, we have not moved beyond calorie restriction in our quest for longer and healthier life.
References
1. McDonald RB, Ramsey JJ. Honoring Clive McCay and 75 years of calorie restriction research. J Nutr. 2010 Jul;140(7):1205-10. doi: 10.3945/jn.110.122804. Epub 2010 May 19. PMID: 20484554; PMCID: PMC2884327.
2. Kenyon C. The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing. Philos Trans R Soc Lond B Biol Sci. 2011 Jan 12;366(1561):9-16. doi: 10.1098/rstb.2010.0276. PMID: 21115525; PMCID: PMC3001308.
3. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5. doi: 10.1038/nature08221. Epub 2009 Jul 8. PMID: 19587680; PMCID: PMC2786175.
4. Kumar, P.; Osahon, O.W.;Sekhar, R.V. GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Mice Increases Length of Life by Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities in Mitophagy and Nutrient Sensing, and Genomic Damage. Nutrients 2022, 14, 1114. https://doi.org/10.3390/nu14051114
5. Kumar P, Liu C, Suliburk J, Hsu JW, Muthupillai R, Jahoor F, Minard CG, Taffet GE, Sekhar RV. Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial. J Gerontol A Biol Sci Med Sci. 2022 Aug 17:glac135. doi: 10.1093/gerona/glac135. Epub ahead of print. PMID: 35975308.
6. Dröge W. Oxidative stress and ageing: is ageing a cysteine deficiency syndrome? Philos Trans R Soc Lond B Biol Sci. 2005 Dec 29;360(1464):2355-72. doi: 10.1098/rstb.2005.1770. PMID: 16321806; PMCID: PMC1569588.
7. Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle. 2006 Sep;5(18):2087-102. doi: 10.4161/cc.5.18.3288. Epub 2006 Sep 15. PMID: 17012837.
8. Hashizume, O., Ohnishi, S., Mito, T. et al. Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. Sci Rep 5, 10434 (2015). https://doi.org/10.1038/srep10434
9. Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, Inman CL, Ogrodnik MB, Hachfeld CM, Fraser DG, Onken JL, Johnson KO, Verzosa GC, Langhi LGP, Weigl M, Giorgadze N, LeBrasseur NK, Miller JD, Jurk D, Singh RJ, Allison DB, Ejima K, Hubbard GB, Ikeno Y, Cubro H, Garovic VD, Hou X, Weroha SJ, Robbins PD, Niedernhofer LJ, Khosla S, Tchkonia T, Kirkland JL. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018 Aug;24(8):1246-1256. doi: 10.1038/s41591-018-0092-9. Epub 2018 Jul 9. PMID: 29988130; PMCID: PMC6082705.
10. Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28. doi: 10.1016/j.ebiom.2018.09.015. Epub 2018 Sep 29. PMID: 30279143; PMCID: PMC6197652.
11. Axel Kowald, Thomas B.L. Kirkwood, Senolytics and the compression of late-life mortality,Experimental Gerontology, Volume 155, 2021,111588,ISSN 0531-5565,https://doi.org/10.1...ger.2021.111588.
12. Bernardes de Jesus B, Vera E, Schneeberger K, Tejera AM, Ayuso E, Bosch F, Blasco MA. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med. 2012 Aug;4(8):691-704. doi: 10.1002/emmm.201200245. Epub 2012 May 15. PMID: 22585399; PMCID: PMC3494070.
13. Muñoz-Lorente, M.A., Cano-Martin, A.C. & Blasco, M.A. Mice with hyper-long telomeres show less metabolic aging and longer lifespans. Nat Commun 10, 4723 (2019). https://doi.org/10.1...467-019-12664-x
14. Kim, D., Kiprov, D.D., Luellen, C. et al. Old plasma dilution reduces human biological age: a clinical study. GeroScience (2022). https://doi.org/10.1...357-022-00645-w
Source: https://www.academia...restriction_yet
Edited by QuestforLife, 01 September 2022 - 11:53 AM.
