Intermittent and periodic fasting, longevity and disease

Abstract

Intermittent and periodic fasting (IF and PF, respectively) are emerging as safe strategies to affect longevity and healthspan by acting on cellular aging and disease risk factors, while causing no or minor side effects. IF lasting from 12 to 48 hours and repeated every 1 to 7 days and PF lasting 2 to 7 days and repeated once per month or less have the potential to prevent and treat disease, but their effect on cellular aging and the molecular mechanisms involved are only beginning to be unraveled. Here, we describe the different fasting methods and their effect on longevity in organisms ranging from yeast to humans, linking them to the major nutrient-sensing signaling pathways and focusing on the benefits of the fasting and the refeeding periods. We also discuss both the therapeutic potential and side effects of IF and PF with a focus on cancer, autoimmunity, neurodegeneration and metabolic and cardiovascular disease.

Fig. 1 |. Fasting, nutrient signaling and longevity in yeast.

Starvation conditions in yeast cause a major lifespan extension mediated in large part by the lack of amino acids and sugars. On one hand, amino-acid restriction causes the inactivation of TOR–Pkh–S6k signaling; on the other hand, low glucose levels promote reduced activity of the Ras–adenylate cyclase (Cyr1)–PKA pathway. Both the amino-acid and the sugar pathways converge on and inactivate the serine threonine kinase Rim15. This, in turn, contributes to the activation of stress-resistance transcription factors Gis1, which binds to post diauxic shift (PDS) motif, and Msn2 and Msn4, orthologs of mammalian early growth response protein 1 (EGR1)^,, which bind to stress-responsive element (STRE) motif.

Fig. 2 |. Conserved nutrient-sensing response pathways in worms, flies and mammals.

This model summarizes the conserved nutrient-sensing pathways that regulate longevity and stress-response mechanisms in different model organisms. Fasting or calorie restriction reduces the activity of amino acids and glucose signaling pathways through membrane receptors by reducing circulating ligands such as growth factors like mammalian IGF-1. The fasting-inhibited TOR–S6K pathway (labeled in blue) promotes the expression of nuclear transcription factors such as the hypoxia-inducible factor-1 (HIF-1), the FOXA ortholog PHA-4, the nuclear hormone receptors NHR-62 and NHR-49 and the TFEB ortholog HLH-30 (worms), the FOXA nuclear factor (flies) and the increase of the FOXO nuclear factor (mammals). These transcription factors commonly activate antiaging systems and processes, including autophagy and ribosomal biogenesis, stress response and cellular-protection genes, including antioxidant SODs. The RAS–AC–PKA pathway (labeled in green) is also partially conserved between species. Similar to what was observed in yeast, glucose in certain mammalian cells can signal through the PKA pathway and the transcription factor EGR1, the mammalian ortholog of Msn2/Msn4 in yeast. In worms, flies and mice, downregulation of TOR–S6K signaling has conserved proaging effects. The fasting-dependent effects on longevity in different organisms may also involve sirtuin pathway activation (labeled in orange), the increase in mitochondria respiration and the activation of autophagy^,. Also, fasting in flies delays the disruption of tricellular junctions (TCJs), which is linked to improved intestinal barrier integrity and therefore longevity (labeled in gray).

Fig. 3 |. Periodic fasting and tissue regeneration and rejuvenation in mice.

Periodic fasting or FMD can affect tissue regeneration in multiple systems and organs in mice. a, In bone marrow, PF or FMD drives self-renewal of HSCs and lineage-balance regeneration of the immune system, leading to a lymphoid-biased phenotype. b, PF and FMD increase mesenchymal stem and progenitor cells (MSPCs) in bone marrow. c, PF and FMD increase neurogenesis in brain tissue, represented by increase in doublecortin (DCX) levels in newly generated bromodeoxyuridine (BrdU⁺) neurons. d, In muscle tissue, PF or FMD modulates the expression of the pair box protein Pax-7, a stem-cell marker mainly expressed by muscle satellite stem cells, and MyoD, a marker of early muscle differentiation. e, In the pancreas, PF and FMD drive increased expression of early developmental markers, including SOX-17, and of the downstream NGN3 transcription factor, leading to the regeneration of insulin-producing β cells. f, In intestinal tissue acute one-day-only fasting, PF and FMD increase levels of ISCs and progenitors in part by inducing a fatty-acid oxidation (FAO) program or by modulating gut microbiota.