aging mice

There’s a lot of confusion and misdirection in the area of diet and aging, so let’s see if we can get some of it straightened out.

mTOR

mTOR is the mammalian target of rapamycin, a molecular mechanism that integrates growth and energy signals.[1] When mTOR is activated by nutrients, it signals the cell to grow.

mTOR is likely very important in promoting aging.

We know this because rapamycin, a drug that extends lifespan in lab animals, inhibits mTOR.[2] The basic idea is that mTOR signaling is vitally important in the growth of an organism, but that its activation after maturity results in aging.

Nutrients activate mTOR. Hence the power of calorie restriction to prolong lifespan: fewer nutrients, less mTOR activation, longer life.

Other lifespan-promoting agents also deactivate mTOR. Metformin, for example.[3] Iron chelators deactivate mTOR.[4] (And of interest, rapamycin interferes with iron metabolism.[5])

What sort of nutrients activate mTOR, and are they equally potent inactivation?

It’s common to read that amino acids (from protein) activate mTOR, and indeed they do, but this is a very incomplete picture.[6]

Hence the obsessive idea in some quarters that dietary protein promotes aging is, if not entirely wrong, incomplete and misleading.

One reason the picture is misleading is that mTOR is intimately linked to insulin, the hormone whose primary purpose is to regulate glucose metabolism. See the illustration below, showing the linkage. Note that glucose also activates mTOR.[7]

Figure 1

Insulin activation is linked to mTOR activation. And what activates insulin the most? Carbohydrates.

IGF-1 signaling is also implicated in aging. Insulin and IGF-1 levels are highly correlated.[8]

Carbohydrates increase the risk of breast cancer recurrence 5-fold in IGF-1 positive cancer by increasing IGF-1 activity.[9]

Fasting

Intermittent fasting promotes a longer lifespan.[10] Fasting appears to have all of the benefits but few of the downsides of calorie restriction.

Fasting activates AMPK, which inhibits mTOR. Note that other antiaging interventions like rapamycin and metformin also activate AMPK.

But, what aspect of fasting activates AMPK? Is it the absence of food altogether, or the absence of a particular macronutrient?

Carbohydrate restriction regulates the adaptive response to fasting.[11]

Human subjects either fasted for 3.5 days, or fasted and got a lipid infusion, and “Changes in plasma glucose, free fatty acids, ketone bodies, insulin, and epinephrine concentrations during fasting were the same in both the control and lipid studies.” 

“These results demonstrate that restriction of dietary carbohydrate, not the general absence of energy intake itself, is responsible for initiating the metabolic response to short-term fasting.”

That’s not to say that protein has no involvement, but it does seem to confirm that the widely circulated pronouncements of certain scientists that protein promotes aging is badly misleading.

One reason that protein is likely to be much less of a concern than carbohydrates foraging is that the ketogenic diet, by definition very low in carbohydrates, extends lifespan.[12]

The ketogenic diet also inhibits mTOR and increases AMPK.[13] This is despite the fact that a ketogenic diet normally contains a full complement of protein, perhaps 10 to 15% of calories, and sometimes more.

Glucose and lifespan

There’s an abundance of evidence, all but ignored, that dietary glucose promotes aging.

Glucose triggers apoptosis in yeast chronological aging.[14]

Glucose restriction extends C. elegans life span by inducing mitochondrial respiration and increasing oxidative stress.[15]

Mice taking the anti-diabetic drug acarbose, which inhibits the absorption of carbohydrates, lived longer, males by 22%.[16]

Humans who took acarbose had a 50% reduction in cardiovascular risk.[17]

The results above are for dietary glucose. Carbohydrates are of course long chains of glucose, which when broken down become glucose in the body. If a person has the least bit of insulin resistance, and often even if they don’t, blood glucose rises.

Then there’s metformin which, next to rapamycin, is considered the best shot at a bona fide life extension drug.[18]

And what does metformin do? It lowers blood glucose and insulin via multiple mechanisms.

A drug that lowers glucose and insulin extends lifespan, showing the critical importance of these two molecules for aging and lifespan.

The OTC supplement glucosamine also extends lifespan, by interfering with glucose metabolism.[19]

Calorie and protein restriction

Some have thought that the effects of calorie restriction may be due to restriction of protein. One piece of evidence for that is that restriction of the single amino acid methionine extends lifespan, and seems to mimic calorie restriction.[20] However, methionine restriction isn’t the same as restricting all protein, and other mechanisms may account for it.

Calorie restriction improves glucose metabolism and lowers insulin levels, but protein restriction does not.[21]

“The effect of dietary restriction on lifespan in rodents is explained by calories alone.”[22]

Valter Longo recommends a vegan diet

Valter Longo, who is perhaps the scientist best known to the public in the field of aging research, recommends a (nearly) vegan diet for longevity.[23]

“Eat mostly vegan, plus a little fish, limiting meals with fish to a maximum of two or three per week… keep protein intake low… Minimize saturated fats from animal and vegetable sources (meat, cheese) and sugar, and maximize good fats and complex carbs.”

Based on what I’ve written above, there doesn’t seem to be a lot of solid backing for Longo’s recommendations. (Other than no sugar.)

He says nothing about avoiding ultra-processed foods, the main dietary cause of disease and early death in the developed world. His low-protein strategy is based on weak epidemiology, and doesn’t take into account all of the evidence laid out above that carbohydrates and glucose have far more to do with aging than protein, which may not matter at all.

Chronic mTOR activation

Activation of mTOR is not a problem for aging, in my view. Chronic activation is.

As we age, we become more insulin resistant, leading to chronically high insulin levels, and chronically activated insulin receptors. As we saw, insulin is connected to mTOR. When insulin increases, mTOR is activated.

Insulin is not a problem. It’s a necessary hormone that is there to do a job. Likewise, mTOR is a necessary molecular mechanism. Chronically activated mTOR promotes aging.

In a glucose tolerance test, 75 grams of glucose (15 teaspoons, a large bolus) are given orally. In a normal person, blood glucose and insulin will return to normal within 2 hours.[24]

If someone were eating all the time, or had insulin resistance due to obesity or some other condition, then glucose and insulin will remain elevated constantly. mTOR would be activated chronically.

Conclusion

A large body of evidence shows that carbohydrates generally, and glucose specifically, are much more important to aging than protein.

A ketogenic diet, by definition low in carbohydrates, extends lifespan. But to my knowledge, no one has ever shown that a vegan diet extends lifespan.

Scientists involved in the study of aging are of course specialized, but there’s an unfortunate tendency for them to ignore diet, other than calorie restriction.

Furthermore, again to my knowledge, no one has ever extended the lifespan of a carnivore by calorie restriction. Only omnivores, eating high-carbohydrate diets, have had their lives extended by calorie restriction.

Vegetarians are not overrepresented among long-lived humans. But people with low insulin resistance – high insulin sensitivity, leading to less chronic activation of mTOR – are.[25]

Dietary carbohydrates promote aging, and protein does less so if at all.

But somehow scientists are not seeing this.

Update: I meant to include the following, very interesting study: Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle. ( Draznin, B., et al. “Effect of dietary macronutrient composition on AMPK and SIRT1 expression and activity in human skeletal muscle.” Hormone and Metabolic Research 44.09 (2012): 650-655.)

Calorie restriction activates AMPK, the cellular energy sensor which deactivates mTOR. CR also activates PGC1 alpha, which promotes mitochondrial biogenesis. Both are key factors in long life.

The study used human volunteers in 4 conditions: overfeeding or underfeeding, each with high carb or low carb diet.

“Our data indicate that a relative deficiency in carbohydrate intake or, albeit less likely, a relative excess of fat intake even in the absence of caloric deprivation is sufficient to activate the AMPK-SIRT 1-PGC1α energy-sensing cellular network in human skeletal muscle. “

This indicates that at least part of the physiological response to calorie restriction comes from a decrease in carbohydrates.

In all dietary conditions, the protein was 20% of calories, which shows that protein has no effect on these responses to calorie restriction. It’s all about carbohydrates.


[1] Laplante, Mathieu, and David M. Sabatini. “mTOR signaling in growth control and disease.” Cell 149.2 (2012): 274-293.

[2] Blagosklonny, Mikhail V. “Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans).” Cell Cycle 9.4 (2010): 683-688.

[3] Sahra, Isaam Ben, et al. “Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1.” Cancer research 71.13 (2011): 4366-4372.

[4] Ohyashiki, Junko H., et al. “The oral iron chelator deferasirox represses signaling through the mTOR in myeloid leukemia cells by enhancing expression of REDD1.” Cancer science100.5 (2009): 970-977.

[5] Maiorano, Annamaria, et al. “Sirolimus interferes with iron homeostasis in renal transplant recipients.” Transplantation82.7 (2006): 908-912.

[6] Tokunaga, Chiharu, Ken-ichi Yoshino, and Kazuyoshi Yonezawa. “mTOR integrates amino acid-and energy-sensing pathways.” Biochemical and biophysical research communications 313.2 (2004): 443-446.

[7] Lamming, Dudley W. “Diminished mTOR signaling: a common mode of action for endocrine longevity factors.” Springerplus3.1 (2014): 735.

[8] Nam, S. Y., et al. “Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone.” International journal of obesity 21.5 (1997): 355.

[9] Emond, Jennifer A., et al. “Risk of breast cancer recurrence associated with carbohydrate intake and tissue expression of IGFI receptor.” Cancer Epidemiology and Prevention Biomarkers 23.7 (2014): 1273-1279.

[10] Honjoh, Sakiko, et al. “Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans.” Nature457.7230 (2009): 726.

[11] Klein, S. A. M. U. E. L., and ROBERT R. Wolfe. “Carbohydrate restriction regulates the adaptive response to fasting.” American Journal of Physiology-Endocrinology and Metabolism 262.5 (1992): E631-E636.

[12] Roberts, Megan N., et al. “A ketogenic diet extends longevity and healthspan in adult mice.” Cell metabolism 26.3 (2017): 539-546.

[13] McDaniel, Sharon S., et al. “The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway.” Epilepsia52.3 (2011): e7-e11.

[14] Ruckenstuhl, Christoph et al. “The sweet taste of death: glucose triggers apoptosis during yeast chronological aging.” Aging vol. 2,10 (2010): 643-9. doi:10.18632/aging.100223

[15] PMID: 17908557

[16] Harrison, David E., et al. “Acarbose, 17‐α‐estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males.” Aging cell 13.2 (2014): 273-282.

[17] Chiasson, Jean-Louis, et al. “Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial.” Jama290.4 (2003): 486-494.

[18] Chiasson, Jean-Louis, et al. “Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial.” Jama290.4 (2003): 486-494.

[19] Weimer, Sandra et al. “D-Glucosamine supplementation extend the life span of nematodes and of aging mice.” Nature communications vol. 5 3563. 8 Apr. 2014, doi:10.1038/ncomms4563

[20] Richie Jr, John P., et al. “Methionine restriction increases blood glutathione and longevity in F344 rats.” The FASEB Journal 8.15 (1994): 1302-1307.

[21] Mitchell, Sharon E et al. “The effects of graded levels of calorie restriction: II. Impact of short term calorie and protein restriction on circulating hormone levels, glucose homeostasis, and oxidative stress in male C57BL/6 mice.” Oncotarget vol. 6,27 (2015): 23213-37. doi:10.18632/oncotarget.4003

[22] Speakman, J. R., Sharon Elizabeth Mitchell, and M. Mazidi. “Calories or protein? The effect of dietary restriction on lifespan in rodents is explained by calories alone.” Experimental Gerontology 86 (2016): 28-38.

[23]  https://valterlongo.com/daily-longevity-diet/

[24] Crofts, Catherine, et al. “Identifying hyperinsulinemia in the absence of impaired glucose tolerance: An examination of the Kraft database.” Diabetes research and clinical practice 118 (2016): 50-57.

[25] Barbieri, Michelangela, et al. “Age‐related insulin resistance: is it an obligatory finding? The lesson from healthy centenarians.” Diabetes/metabolism research and reviews17.1 (2001): 19-26.