Cliffnotes: Molecular targets downstream of CR

A very brief list and not a comprehensive one follows. I focus on direct evidence from KO models and lifespan studies, because this is the most robust study design. I don't care for surrogate endpoints, with the exception of pathology. The most common study design can be summarized thusly: When you combine "Factor X" with CR, does this affect the magnitude of LS extension from CR? Where X is either a gain of function (e.g. other LS extension) or loss of function (usually KO) intervention.

A. Direct evidence
B. Indirect evidence
C. Speculative or parallel pathways

A. Direct evidence


CR is not additive with GHRKO:
Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction.
Bonkowski MS, Rocha JS, Masternak MM, Al Regaiey KA, Bartke A
Proc Natl Acad Sci U S A. 2006 May 16; 103(20):7901-5.

PLoS One. 2009;4(2):e4567. doi: 10.1371/journal.pone.0004567. Epub 2009 Feb 23.
Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity. Bonkowski et al.

but it is additive with GHRH(sic) KO:
Elife. 2013 Oct 29;2:e01098. doi: 10.7554/eLife.01098.
Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice.
Sun LY1, Spong A, Swindell WR, Fang Y, Hill C, Huber JA, Boehm JD, Westbrook R, Salvatori R, Bartke A.

and dwarfism:
Extending the lifespan of long-lived mice.
Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS
Nature. 2001 Nov 22; 414(6862):412.

Neuropeptide Y: involved in hypothalamic nutrient sensing

A key role for neuropeptide Y in lifespan extension and cancer suppression via dietary restriction.
Chiba T, Tamashiro Y, Park D, Kusudo T, Fujie R, Komatsu T, Kim SE, Park S, Hayashi H, Mori R, Yamashita H, Chung HY, Shimokawa I.
Sci Rep. 2014 Mar 31;4:4517. doi: 10.1038/srep04517.

Trends Neurosci. 2015 Nov;38(11):701-11. doi: 10.1016/j.tins.2015.08.012.
Neuropeptide Y: An Anti-Aging Player?
Botelho M1, Cavadas C2.

Nrf2: mostly responsible for cancer prevention

Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction.
Pearson KJ, Lewis KN, Price NL, Chang JW, Perez E, Cascajo MV, Tamashiro KL, Poosala S, Csiszar A, Ungvari Z, Kensler TW, Yamamoto M, Egan JM, Longo DL, Ingram DK, Navas P, de Cabo R.
Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2325-30. doi: 10.1073/pnas.0712162105. Epub 2008 Feb 19.

FoxO3: necessary for lifespan but not chemoprevention?
"These results indicate the necessity of Foxo3 for lifespan extension but not cancer suppression by DR. The findings in Foxo3(+/-) mice contrast with those in Foxo1(+/-) mice reported previously by our laboratory suggest differential regulation of cancer and lifespan by DR via Foxo1 and Foxo3."

Shimokawa, I., Komatsu, T., Hayashi, N., Kim, S. E., Kawata, T., Park, S., ... & Mori, R. (2015). The life‐extending effect of dietary restriction requires Foxo3 in mice. Aging cell.

FoxO1: cancer prevention
downstream of PI3K-Akt and responsible for cancer prevention and oxidative stress mamagment.

Aging Cell. 2010 Jun;9(3):372-82. doi: 10.1111/j.1474-9726.2010.00563.x. Epub 2010 Mar 6.
FoxO1 is involved in the antineoplastic effect of calorie restriction.
Yamaza H, Komatsu T, Wakita S, Kijogi C, Park S, Hayashi H, Chiba T, Mori R, Furuyama T, Mori N, Shimokawa I.

Mechanism via autophagy?
CAVE: very small sample size, study aborted before median LS

PLoS One. 2008 Mar 12;3(3):e1759. doi: 10.1371/journal.pone.0001759.
SirT1 regulates energy metabolism and response to caloric restriction in mice.
Boily G1, Seifert EL, Bevilacqua L, He XH, Sabourin G, Estey C, Moffat C, Crawford S, Saliba S, Jardine K, Xuan J, Evans M, Harper ME, McBurney MW.

NB: acceptable maxLS, data convincing at a quick glance
Mercken EM, et al. SIRT1 but not its increased expression is essential for lifespan extension in caloric-restricted mice. Aging Cell. 2014;13(1):193–196.

Lipid composition/fat source:Lard better than soy better than fish source. Impressive!
Lopez-Dominguez et al. (2015). The influence of dietary fat source on life span in calorie restricted mice. J Gerontol A Biol Sci Med Sci 70, 1181–1188.

No added benefiit from exercise: same pathway, overriding effect?
Holloszy, JO (1997) Mortality rate and longevity of food-restricted exercising male rats: a re-evaluation. Am J Physiol 82, 399–403.

Fat tissue

B. indirect evidence

Thyroid hormones, core body temperature, AMPK, adipokines/inflammation, autophagy, complex I modulation, hydrogen sulfide (at least in the acute setting?) etc...


Aging Cell. 2014 Dec;13(6):1012-8. doi: 10.1111/acel.12264. Epub 2014 Aug 26.
ATF4 activity: a common feature shared by many kinds of slow-aging mice.
Li W, Li X, Miller RA.


Highly plausible, but am not aware of direct evidence from KO or similar.

C. speculative or parallel pathways

May be a parallel pathway

Slack, C., Alic, N., Foley, A., Cabecinha, M., Hoddinott, M. P., & Partridge, L. (2015). The Ras-Erk-ETS-Signaling pathway is a drug target for longevity. Cell, 162(1), 72-83.


Reduced expression of MYC increases longevity and enhances healthspan.
Hofmann JW, Zhao X, De Cecco M, Peterson AL, Pagliaroli L, Manivannan J, Hubbard GB, Ikeno Y, Zhang Y, Feng B, Li X, Serre T, Qi W, Van Remmen H, Miller RA, Bath KG, de Cabo R, Xu H, Neretti N, Sedivy JM.
Cell. 2015 Jan 29;160(3):477-88. doi: 10.1016/j.cell.2014.12.016. Epub 2015 Jan 22.

References & further reading

1. Cold Spring Harb Perspect Med. 2015 Nov 2;5(11). pii: a025114. doi: 10.1101/cshperspect.a025114.
Biochemical Genetic Pathways that Modulate Aging in Multiple Species.
Bitto A1, Wang AM1, Bennett CF1, Kaeberlein M1.

2. The Future of Aging: Pathways to Human Life Extension. c.f. chapter by Spindler