Dietary restriction with adequate nutrition is the gold standard for delaying ageing and extending healthspan and lifespan in diverse species, including rodents and non-human primates. In this Review, we discuss the effects of dietary restriction in these mammalian model organisms and discuss accumulating data that suggest that dietary restriction results in many of the same physiological, metabolic and molecular changes responsible for the prevention of multiple ageing-associated diseases in humans. We further discuss how different forms of fasting, protein restriction and specific reductions in the levels of essential amino acids such as methionine and the branched-chain amino acids selectively impact the activity of AKT, FOXO, mTOR, nicotinamide adenine dinucleotide (NAD+), AMP-activated protein kinase (AMPK) and fibroblast growth factor 21 (FGF21), which are key components of some of the most important nutrient-sensing geroprotective signalling pathways that promote healthy longevity.
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The authors specially thank A.Y.X. Dai for helping with the creation of figures. The Lamming laboratory is supported by the US National Institute on Aging (AG056771, AG061635 and AG062328 to D.W.L.), the US National Institute of Diabetes and Digestive and Kidney Diseases (DK125859 to D.W.L.), and by funding from the University of Wisconsin-Madison School of Medicine and Public Health and Department of Medicine to D.W.L. C.L.G. is a Glenn Foundation for Medical Research Postdoctoral Fellow. The Lamming laboratory and C.L.G. were supported in part by a generous gift from Dalio Philanthropies. The Lamming laboratory is also supported by the US Department of Veterans Affairs (I01-BX004031), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. The Fontana laboratory is supported by grants from the Australian National Health and Medical Research Council Investigator Grants programme (APP1177797), the Australian Youth and Health Foundation and the Bakewell Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health, the US Department of Veterans Affairs or the US Government. The authors apologize for the omission of relevant work owing to space constraints.
D.W.L. has received funding from and is a scientific advisory board member of Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. The University of Wisconsin-Madison has applied for a patent for the use of amino acid-restricted diets to promote metabolic health, for which D.W.L. is an inventor. The remaining authors declare no competing interests.
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- Hazard ratio
A comparison between the probability of events in a treatment group and the probability of events in a control group.
- Kaplan–Meier estimated survival
Kaplan–Meier estimated survival or the Kaplan–Meier estimator, also known as the product limit estimator, is a non-parametric statistic used to estimate the survival function from lifetime data. It measures and generates statistics for the fraction of a designated population that is alive at a certain time point.
Age-related hearing loss.
- Cochlear ganglion cells
A group of neurons in the conical central axis of the cochlea. These bipolar neurons innervate the hair cells of the organ of Corti.
Age-related skeletal muscle loss.
- NLRP3 inflammasome
A critical component of the innate immune system that mediates caspase 1 activation and the secretion of the proinflammatory cytokines IL-1β and IL-18 in response to infections or cellular damage.
An enzyme that can break down proteins that are normally found in the spaces between cells in tissues and that is involved in wound healing, angiogenesis and tumour cell metastasis.
A mitotic checkpoint serine/threonine protein kinase, an enzyme that is an essential component of the mitotic checkpoint, required for normal mitosis progression.
A condition in which there are excess levels of insulin circulating in the blood relative to the level of glucose, usually associated with insulin resistance.
When a breast cancer is human epidermal growth factor receptor 2 (HER2)-negative, it means that the cancerous cells do not contain high levels of HER2.
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Green, C.L., Lamming, D.W. & Fontana, L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat Rev Mol Cell Biol (2021). https://doi.org/10.1038/s41580-021-00411-4