9 replies to this topic

[QuestforLife]

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.

[Avatar of Horus]

...
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.

 

This is like this:

 
source: an older post from X.

[Mind]

I agree, we do not have anything as of yet that can beat a healthy lower calorie diet (which can include CR) and exercise.

[Cloomis]

I'm skeptical CR can bring the benefits claimed to humans. It's not universally beneficial in animal tests -- fails in wild strains, and low BMI people do not show increased lifespan.

 

The Calorie Restriction Myth

[QuestforLife]

This is not a argument in favour of CR, which no doubt as your say has limitations, but that we need to find ways of extending lifespan that work through different mechanisms. As the Scooby cartoon shows, it is easy to fool yourself.

[Mind]

I'm skeptical CR can bring the benefits claimed to humans. It's not universally beneficial in animal tests -- fails in wild strains, and low BMI people do not show increased lifespan.

 

The Calorie Restriction Myth

 

I agree for the most part. There is no solid data to indicate that CR will increase lifespan in humans, but most CR practitioners seem to be in good health and live fairly long.

 

As far the "lower calorie diet" comment I made earlier, this is in regards to the vast majority of people in the modern day and in the US in particular. Most people are overweight or obese. They would all be better off with fewer (and higher quality) calories. Not CR necessarily, but a more optimal calorie intake - and the research is very conclusive on this point.

[Avatar of Horus]

I intended to post these in the Aging theories forum section, but they fit here as well:

Some clinical trial data:
"Metabolic Slowing and Reduced Oxidative Damage with Sustained Caloric Restriction Support the Rate of Living and Oxidative Damage Theories of Aging - 2018 Apr 3
https://pubmed.ncbi....h.gov/29576535/

Abstract
Calorie restriction (CR) is a dietary intervention with potential benefits for healthspan improvement and lifespan extension. In 53 (34 CR and 19 control) non-obese adults, we tested the hypothesis that energy expenditure (EE) and its endocrine mediators are reduced with a CR diet over 2 years. Approximately 15% CR was achieved over 2 years, resulting in an average 8.7 kg weight loss, whereas controls gained 1.8 kg. In the CR group, EE measured over 24 hr or during sleep was approximately 80-120 kcal/day lower than expected on the basis of weight loss, indicating sustained metabolic adaptation over 2 years. This metabolic adaptation was accompanied by significantly reduced thyroid axis activity and reactive oxygen species (F2-isoprostane) production. Findings from this 2-year CR trial in healthy, non-obese humans provide new evidence of persistent metabolic slowing accompanied by reduced oxidative stress, which supports the rate of living and oxidative damage theories of mammalian aging.
Trial registration: ClinicalTrials.gov NCT00427193 NCT02695511."

2 comment articles:
"Reduced-calorie diet shows signs of slowing ageing in people - 2018 Mar 29
https://pubmed.ncbi....h.gov/29595781/
https://www.nature.c...586-018-03431-x

Most comprehensive study yet demonstrates that cutting people’s energy intake dials down their metabolism.
A study of people who reduced the calories they consumed has found the strongest evidence yet that such restrictions can slow down human metabolism. The results raise hopes that a low-calorie lifestyle - or treatments that mimic the biological effects of restricted eating - could prolong health in old age and even extend life."
and:
"Sustained caloric restriction in health - 2018 Jun
https://pubmed.ncbi....h.gov/29651021/
https://www.nature.c...1574-018-0008-2

In humans, there are few randomized controlled clinical trials investigating the effects of caloric restriction in health and ageing. Now, ... report the results of a 2-year clinical trial that investigated the effect of caloric restriction in healthy humans.
...
participants in the caloric restriction group had reductions in levels of reactive oxygen species and decreases in thyroid activity (reduced levels of T3 and T4), which is a biomarker of decreased ageing.
The ultimate study into effects of caloric restriction would be one where participants eat a calorie-restricted diet from early adulthood for the remainder of their lives ... Such a study is the only way to truly answer the question of whether caloric restriction extends lifespan and improves healthspan in people."

I am unsure about the early adulthood start.

---

another important point is that: "... the 10-yr risk of CVD-disease was reduced by 30% ... In conclusion, sustained CR in healthy, nonobese individuals is beneficial in improving risk factors for cardiovascular and metabolic disease such as visceral adipose tissue mass, ectopic lipid accumulation, blood pressure, and lipid profile ...", from:

"Significant improvement in cardiometabolic health in healthy nonobese individuals during caloric restriction-induced weight loss and weight loss maintenance - 2018 Apr 1
https://pubmed.ncbi....h.gov/29351490/

Calorie restriction (CR) triggers benefits for healthspan including decreased risk of cardiometabolic disease (CVD). In an ancillary study to CALERIE 2, a 24-mo 25% CR study, we assessed the cardiometabolic effects of CR in 53 healthy, nonobese (BMI: 22-28 kg/m2) men ( n = 17) and women ( n = 36). The aim of this study was to investigate whether CR can reduce risk factors for CVD and insulin resistance in nonobese humans and, moreover, to assess whether improvements are exclusive to a period of weight loss or continue during weight maintenance. According to the energy balance method, the 25% CR intervention ( n = 34) produced 16.5 ± 1.5% (mean ± SE) and 14.8 ± 1.5% CR after 12 and 24 mo (M12, M24), resulting in significant weight loss (M12 -9 ± 0.5 kg, M24 -9 ± 0.5 kg, P < 0.001). Weight was maintained in the group that continued their habitual diet ad libitum (AL, n = 19). In comparison to AL, 24 mo of CR decreased visceral (-0.5 ± 0.01 kg, P < 0.0001) and subcutaneous abdominal adipose tissue (-1.9 ± 0.2kg, P < 0.001) as well as intramyocellular lipid content (-0.11 ± 0.05%, P = 0.031).
Furthermore, CR decreased blood pressure (SBP -8 ± 3 mmHg, P = 0.005; DBP -6 ± 2 mmHg, P < 0.001), total cholesterol (-13.6 ± 5.3 mg/dl, P = 0.001), and LDL-cholesterol (-12.9 ± 4.4 mg/dl, P = 0.005), and the 10-yr risk of CVD-disease was reduced by 30%. Homeostasis model assessment of insulin resistance (HOMA-IR) decreased during weight loss in the CR group (-0.46 ± 0.15, P = 0.003), but this decrease was not maintained during weight maintenance (-0.11 ± 0.15, P = 0.458). In conclusion, sustained CR in healthy, nonobese individuals is beneficial in improving risk factors for cardiovascular and metabolic disease such as visceral adipose tissue mass, ectopic lipid accumulation, blood pressure, and lipid profile, whereas improvements in insulin sensitivity were only transient."

[Cloomis]

The CALERIE study participants may have been non-obese, but they were on average overweight (25.7 BMI). Yes, losing some weight would be good for them. In any case, CVD is only one mortality cause, and over-optimization on one factor can increase all-cause mortality. At the end, they weren't really effectively doing CR, if I remember right.

 

Continued CR would drop weight below 20 BMI, and observationally, that increases mortality in humans.

[Rocket]

I think calorie restriction extends life in humans a few years at best. I tried it for a few years. It most certainly has positive effects in cardiovascular health, but there are other less severe ways to keep healthy than starving yourself. Since it doesn't actually slow aging I moved on to metformin and rapamycin as the best means available today for a longer healthier life

[Mind]

I think calorie restriction extends life in humans a few years at best. I tried it for a few years. It most certainly has positive effects in cardiovascular health, but there are other less severe ways to keep healthy than starving yourself. Since it doesn't actually slow aging I moved on to metformin and rapamycin as the best means available today for a longer healthier life

 

Rocket hits on something important - quality of life.

 

Remaining in semi-starvation for many years at a time is not appealing to many people. I would like to find ways to reverse aging so that I can enjoy treats once in a while. I don't want to give up every treat in life, just to add a couple of extra years.