What causes aging and how does dietary restriction increase life span?

The only environmental factor known to increase life expectancy in organisms from invertebrates to humans is dietary restriction, that is, a reduction in food consumption without malnutrition.

While this was first discovered over 70 years ago, the mechanism behind increased life span by calorie restriction has eluded us.  Here, I discuss the mechanism that I find to be the most consistent and plausible; glucose hysteresis.

Glucose hysteresis was implicated as a possible cause of aging by Mobbs et al. in the 2007 paper, “Glucose Hysteresis as a Mechanism in Dietary Restriction, Aging, and Disease.” Hysteresis describes a state in which certain genes are “switched” on or off by some metabolite, and the genes tend to remain in that state. That is, the genes have a sort of “memory.” In the case of glucose hysteresis, glucose is the metabolite involved in up- or down-regulating the expression of certain genes.

Metabolites, like glucose, can induce changes in an organism’s gene expression in order to make the utilization of that metabolite more efficient (1,2).  This allows the organism’s molecular machinery to optimize the metabolism of that fuel source. There is evidence that these genes remain up-regulated even after the fuel source has been used up (3-7). This way, the organism is prepared to efficiently utilize that fuel source in the future.

The body uses different machinery to break down different fuel sources. When carbohydrates are consumed, they are broken down into glucose. Then, glucose is further broken down in a process called glycolysis.  The end products of glycolysis are mainly dependent on an enzyme called mitochondrial complex I to complete the metabolism.

When fats are consumed, they undergo beta-oxidation, which can be thought of as the equivalent of glycolysis for fats. The end products of this process are mainly dependent on mitochondrial complex II to complete metabolism.

Complex I (needed for glucose metabolism) produces more reactive oxygen species (ROS) than complex II (needed for fat metabolism) (8-10). ROS are highly reactive molecules that cause oxidative damage and can promote aging. It is thought that life extension through dietary restriction is a result of decreased oxidative damage (11-14).

During dietary restriction, glycolysis is reduced and lipid metabolism is increased. As people age, the opposite occurs (15). Several studies have shown that reducing glycolysis increases life span, while increasing glycolysis decreases life span (16-19).

Metabolism of fats rather than glucose has advantages other than just reducing the amount of ROS produced. The breakdown of fats produces the antioxidant NADPH, which can help prevent oxidative stress in the body. Furthermore, when fat metabolism is up-regulated, there is a greater turnover rate of fats and proteins, thereby reducing the accumulation of oxidized fatty acids (20).

Thus, according to the glucose hysteresis hypothesis, consumption of glucose leads to an up-regulation of the glycolysis machinery. Over time, the body becomes more adapted to metabolizing glucose for fuel rather than fats and proteins. This leads to increased ROS production, reduced antioxidant production, greater accumulation of oxidized fatty acids, and ultimately increases the rate of aging.

According to this hypothesis, by reducing glucose consumption and increasing fat consumption people could “reprogram” their gene expression and increase their life span.

While there is strong evidence backing this hypothesis, the authors note that further study is needed to confirm it. For example, a study should be done where plasma glucose is permanently lowered using genetic manipulation. If the glucose hysteresis hypothesis is accurate, this should produce the same life span increasing effects as dietary restriction.

If proven correct, glucose restriction could offer a promising way to increase life span. However, this hypothesis may be slow to gain traction as it goes directly against the “common knowledge” today that a healthy diet consists primarily of carbohydrates with moderate protein and little fat.

Lastly, I should note that carbohydrates can provide benefits, such as increasing athletic performance. Sources of carbohydrates like fruits and vegetables can provide vitamins and antioxidants. So, a cost-benefit analysis is needed on an individual basis to determine the optimal amount of carbohydrates in the diet.


1. Roche E, Assimacopoulos-Jeannet F, Witters LA, Perruchoud B, Yaney G, Corkey B, Asfari M, Prentki M. Induction by glucose of genes coding for glycolytic enzymes in a pancreatic beta-cell line (INS-1). J Biol Chem 1997;272:3091–3098. [PubMed: 9006960]

2. Abbot EL, McCormack JG, Reynet C, Hassall DG, Buchan KW, Yeaman SJ. Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells. FEBS J 2005;272:3004–3014. [PubMed: 15955060]

3. Mobbs, CV. Neurohumoral hysteresis as a mechanism for senescence: comparative aspects. In: Scanes, CG.; Schriebman, MP., editors. Development, Maturation, and Senescence of the Neuroendocrine System. Academic Press; New York: 1989. p. 223-252.

4. Mobbs CV. Neurotoxic effects of estrogen, glucose, and glucocorticoids: neurohumoral hysteresis and its pathological consequences during aging. Rev Biol Res Aging 1990;4:201–228.

5. Mobbs CV. Genetic influences on glucose neurotoxicity, aging, and diabetes: a possible role for glucose hysteresis. Genetica 1993;91:239–253. [PubMed: 8125273]

6. Mobbs CV. Molecular hysteresis: residual effects of hormones and glucose on genes during aging. Neurobiol Aging 1994;15:523–534. [PubMed: 7969735]

7. Pfaff DW, Brooks PJ, Funabashi T, Pfaus JG, Mobbs CV. Gene memory in neuroendocrine and behavioural systems. Ciba Found Symp 1992;168:165–183. [PubMed: 1425024]

8. Herrero A, Barja G. Localization of the site of oxygen radical generation inside the complex I of heart and nonsynaptic brain mammalian mitochondria. J Bioenerg Biomembr 2000;32:609–615. [PubMed: 15254374]

9. Lenaz G. The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life 2001;52:159–164. [PubMed: 11798028]

10. Barja G. Aging in vertebrates, and the effect of caloric restriction: a mitochondrial free radical production-DNA damage mechanism? Biol Rev Camb Philos Soc 2004;79:235–251. [PubMed: 15191224]

11. Johnson TE, Cypser J, de Castro E, de Castro S, Henderson S, Murakami S, Rikke B, Tedesco P, Link C. Gerontogenes mediate health and longevity in nematodes through increasing resistance to environmental toxins and stressors. Exp Gerontol 2000;35:687–694. [PubMed: 11053658]

12. Obici S, Feng Z, Tan J, Liu L, Karkanias G, Rossetti L. Central melanocortin receptors regulate insulin action. J Clin Invest 2001;108:1079–1085. [PubMed: 11581309]

13. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science 1996;273:59–63. [PubMed: 8658196]

14. Lass A, Sohal BH, Weindruch R, Forster MJ, Sohal RS. Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria. Free Radic Biol Med 1998;25:1089–1097. [PubMed: 9870563]

15. Lee CK, Allison DB, Brand J, Weindruch R, Prolla TA. Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc Natl Acad Sci USA 2002;99:14988– 14993. [PubMed: 12419851]

16. Hamilton B, Dong Y, Shindo M, Liu W, Odell I, Ruvkun G, Lee SS. A systematic RNAi screen for longevity genes in C. elegans. Genes Dev 2005;19:1544–1555. [PubMed: 15998808]

17. Hansen M, Hsu AL, Dillin A, Kenyon C. New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLos Genet 2005;1:119– 128. [PubMed: 16103914]

18. Lopez-Torres M, Gredilla R, Sanz A, Barja G. Influence of aging and long-term caloric restriction on oxygen radical generation and oxidative DNA damage in rat liver mitochondria. Free Radic Biol Med 2002;32:882–889. [PubMed: 11978489]

19. Hansson A, Hance N, Dufour E, Rantanen A, Hultenby K, Clayton DA, Wibom R, Larsson NG. A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts. Proc Natl Acad Sci USA 2004;101:3136–3141. [PubMed: 14978272]

20. Mobbs CV, Mastaitis J, Zhang M, Isoda F, Cheng H, Yen K. Glucose hysteresis as a mechanism in dietary restriction, aging and disease. Interdiscip Top Gerontol. 2007; 39-68.

6 thoughts on “What causes aging and how does dietary restriction increase life span?

  1. Pingback: HubMed: Pubmed goes social | TimBatchelder.com: Bio, Clean + Social Technologies

  2. An update:

    A new study from the National Institute of Aging (NIA) found no effect of dietary restriction on life span in rhesus monkeys. This contradicts the results of a similar study released in 2009 from the University of Wisconsin.

    The new study by the NIA did find a reduction or delayed onset of cancer, diabetes, arthritis and cardiovascular problems in calorically restricted monkeys.

    For those interested, the diet in the NIA study was composed of 72% carbohydrate, 22% protein, and 6% fat.

    • Hey Mike- very thoughtful post that Jaminet put out. I’m generally in agreement with him.

      I don’t buy his argument that evolution is selecting for longevity in humans. The goal in evolution is to live long enough to ensure the survival of the next generation.

      I think for maximum longevity, eating few carbohydrates would be beneficial. But, carbohydrates might improve our quality of life. So, one must weight out the pros and cons.

      Overall, I think eliminating the junk in our diets is the place to start. There’s much debate over the little stuff. The quality of the food makes the real difference.

      • Agreed Bill. Paul actually does say that the carb quantity is not a massive factor, it’s just a factor. I agree about pros and cons, I read that in your article above, and Paul does have another article that talks about carbs of 30% prob best for longevity, 40% neutral, and 50% best for fertility. He also notes that all over the world, people tend to go for about 50% carbs when food is abundant. That’s huge I think. Keep up the good work! ~ Mike

  3. Pingback: Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation « Pharmaceutical Intelligence

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