Every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice

Abstract

Dietary restriction regimes extend lifespan in various animal models. Here we show that longevity in male C57BL/6J mice subjected to every-other-day feeding is associated with a delayed onset of neoplastic disease that naturally limits lifespan in these animals. We compare more than 200 phenotypes in over 20 tissues in aged animals fed with a lifelong every-other-day feeding or ad libitum access to food diet to determine whether molecular, cellular, physiological and histopathological aging features develop more slowly in every-other-day feeding mice than in controls. We also analyze the effects of every-other-day feeding on young mice on shorter-term every-other-day feeding or ad libitum to account for possible aging-independent restriction effects. Our large-scale analysis reveals overall only limited evidence for a retardation of the aging rate in every-other-day feeding mice. The data indicate that every-other-day feeding-induced longevity is sufficiently explained by delays in life-limiting neoplastic disorders and is not associated with a more general slowing of the aging process in mice.

Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories

“…The modest, but significant extension of longevity in MF animals, associated with delayed onset of fatty liver disease and hepatocellular carcinoma, re-opens the issue of the relative importance of reduced caloric intake per se in the beneficial effects of CR as opposed to periods of fasting that occur as a result of lower food intake (Acosta-Rodriguez et al, 2017; Masoro, 2004). This work extends previous important findings from our laboratory (Anson et al, 2003) and others (Chaix et al, 2014; Xie et al, 2017). Because most humans already have about a 8 to 12h night fast built into their day, a longer daily fasting period may be required to confer health and survival benefits.…”

The hidden costs of dietary restriction: Implications for its evolutionary and mechanistic origins

“…Studies in the previous century on rodents already demonstrated that inducing intermittent fasting, by feeding animals every other day or by other means, extends life span in a similar manner to caloric restriction [reviewed in (47)]. Two recent studies in mice suggest the same, although the effects are not as large as full caloric restriction (48), and outcomes for systemic ageing have been questioned (49). Human data on intermittent fasting are promising (46) and have on July 4, 2020 http://advances.sciencemag.org/ Downloaded from potential application in specific diseases (50), but conclusive evidence from clinical trials is currently lacking (51).…”

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

“…Indeed, as described in the previous section, we observed weight loss in mice with diet-induced obesity subjected to intermittent fasting with preservation of β-cell mass despite continued high fat feeding and restoration of β-cell function (119). In another study of chronic intermittent fasting in both young and aged mice, an every other day fasting regimen prolonged lifespan, reduced left ventricular mass and attenuated ageing-induced cardiac hypertrophy, and improved glucose tolerance (240), but did not affect other metabolic parameters in young mice, pointing to an important interaction between age at which the intermittent fasting regimen was initiated and metabolic outcomes. An important note of caution is the observation for increased insulin resistance with every other day fasting regimens in young obese mice in our studies (119), which was mirrored by a trend towards increased circulating insulin levels in young mice (240) as well as evidence for increased hepatic insulin resistance in rats (157).…”

“…In another study of chronic intermittent fasting in both young and aged mice, an every other day fasting regimen prolonged lifespan, reduced left ventricular mass and attenuated ageing-induced cardiac hypertrophy, and improved glucose tolerance (240), but did not affect other metabolic parameters in young mice, pointing to an important interaction between age at which the intermittent fasting regimen was initiated and metabolic outcomes. An important note of caution is the observation for increased insulin resistance with every other day fasting regimens in young obese mice in our studies (119), which was mirrored by a trend towards increased circulating insulin levels in young mice (240) as well as evidence for increased hepatic insulin resistance in rats (157). These findings suggest that the duration of fasting may be a stress, and will need to be carefully titrated depending upon the species (as 24 hours of fasting in a mouse is perhaps equivalent to a much longer period of fast in humans given differences in lifespan).…”

“…Nonetheless, sustained alterations in cardiac metabolism can lead to prolonged activation of mTOR with adverse consequences (reviewed in Sciarretta et al (180)). While unopposed stimulation of the LYNUS ( Ly sosomal Nu trient S ensing complex)-mTOR axis can provoke contractile dysfunction in cardiometabolic disease states (182, 198, 250), accumulating experimental evidence from our lab and others indicates that cyclic activation and inactivation of this pathway during periods of feeding and fasting may restore cellular homeostasis, in a manner that depends on intact autophagy and lysosomal function (72) (13, 119), Indeed, studies from C. elegans to humans support the notion that fasting strategies prolong lifespan, prevent life-threatening illnesses such as cancer, stimulate cellular regeneration and enhance the ability of organisms to endure subsequent stress (25, 39, 76, 88, 229, 240). In addition, markers of aging and senescence also appear to decrease in models of intermittent fasting (25).…”