A Periodic Diet That Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2015 Jun 23

PMID 26094889

Citations 399

Authors

Sebastian Brandhorst

In Young Choi

Min Wei

Chia Wei Cheng

Sargis Sedrakyan

Gerardo Navarrete

Louis Dubeau

Li Peng Yap

Ryan Park

Manlio Vinciguerra

Stefano Di Biase

Hamed Mirzaei

Mario G Mirisola

Patra Childress

Lingyun Ji

Susan Groshen

Fabio Penna

Patrizio Odetti

Laura Perin

Peter S Conti

Yuji Ikeno

Brian K Kennedy

Pinchas Cohen

Todd E Morgan

Tanya B Dorff

Valter D Longo

Affiliations

Soon will be listed here.

Abstract

Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.

Citing Articles

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References

Muller-Sieburg C, Cho R, Karlsson L, Huang J, Sieburg H . Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness. Blood. 2004; 103(11):4111-8. DOI: 10.1182/blood-2003-10-3448. View

Beninger R, Jhamandas K, Boegman R, El-Defrawy S . Effects of scopolamine and unilateral lesions of the basal forebrain on T-maze spatial discrimination and alternation in rats. Pharmacol Biochem Behav. 1986; 24(5):1353-60. DOI: 10.1016/0091-3057(86)90195-4. View

Barnes C . Spatial learning and memory processes: the search for their neurobiological mechanisms in the rat. Trends Neurosci. 1988; 11(4):163-9. DOI: 10.1016/0166-2236(88)90143-9. View

Sharma A, Moore M, Marcora E, Lee J, Qiu Y, Samaras S . The NeuroD1/BETA2 sequences essential for insulin gene transcription colocalize with those necessary for neurogenesis and p300/CREB binding protein binding. Mol Cell Biol. 1998; 19(1):704-13. PMC: 83927. DOI: 10.1128/MCB.19.1.704. View

Wullschleger S, Loewith R, Hall M . TOR signaling in growth and metabolism. Cell. 2006; 124(3):471-84. DOI: 10.1016/j.cell.2006.01.016. View

Cuervo A, Bergamini E, Brunk U, Droge W, Ffrench M, Terman A . Autophagy and aging: the importance of maintaining "clean" cells. Autophagy. 2006; 1(3):131-40. DOI: 10.4161/auto.1.3.2017. View

Morgan T, Wong A, Finch C . Anti-inflammatory mechanisms of dietary restriction in slowing aging processes. Interdiscip Top Gerontol. 2006; 35:83-97. DOI: 10.1159/000096557. View

Kaeberlein T, Smith E, Tsuchiya M, Welton K, Thomas J, Fields S . Lifespan extension in Caenorhabditis elegans by complete removal of food. Aging Cell. 2006; 5(6):487-94. DOI: 10.1111/j.1474-9726.2006.00238.x. View

Smith E, Kaeberlein T, Lydum B, Sager J, Welton K, Kennedy B . Age- and calorie-independent life span extension from dietary restriction by bacterial deprivation in Caenorhabditis elegans. BMC Dev Biol. 2008; 8:49. PMC: 2408926. DOI: 10.1186/1471-213X-8-49. View

10.

Raffaghello L, Lee C, Safdie F, Wei M, Madia F, Bianchi G . Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci U S A. 2008; 105(24):8215-20. PMC: 2448817. DOI: 10.1073/pnas.0708100105. View

11.

Brown-Borg H . Hormonal control of aging in rodents: the somatotropic axis. Mol Cell Endocrinol. 2008; 299(1):64-71. PMC: 4390024. DOI: 10.1016/j.mce.2008.07.001. View

12.

Roybon L, Hjalt T, Stott S, Guillemot F, Li J, Brundin P . Neurogenin2 directs granule neuroblast production and amplification while NeuroD1 specifies neuronal fate during hippocampal neurogenesis. PLoS One. 2009; 4(3):e4779. PMC: 2652712. DOI: 10.1371/journal.pone.0004779. View

13.

Greer E, Brunet A . Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell. 2009; 8(2):113-27. PMC: 2680339. DOI: 10.1111/j.1474-9726.2009.00459.x. View

14.

Bellantuono I, Aldahmash A, Kassem M . Aging of marrow stromal (skeletal) stem cells and their contribution to age-related bone loss. Biochim Biophys Acta. 2009; 1792(4):364-70. DOI: 10.1016/j.bbadis.2009.01.008. View

15.

Kasper G, Mao L, Geissler S, Draycheva A, Trippens J, Kuhnisch J . Insights into mesenchymal stem cell aging: involvement of antioxidant defense and actin cytoskeleton. Stem Cells. 2009; 27(6):1288-97. DOI: 10.1002/stem.49. View

16.

Clelland C, Choi M, Romberg C, Clemenson Jr G, Fragniere A, Tyers P . A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009; 325(5937):210-3. PMC: 2997634. DOI: 10.1126/science.1173215. View

17.

Harrison D, Strong R, Sharp Z, Nelson J, Astle C, Flurkey K . Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009; 460(7253):392-5. PMC: 2786175. DOI: 10.1038/nature08221. View

18.

Narasimhan S, Yen K, Tissenbaum H . Converging pathways in lifespan regulation. Curr Biol. 2009; 19(15):R657-66. PMC: 3109866. DOI: 10.1016/j.cub.2009.06.013. View

19.

Gao Z, Ure K, Ables J, Lagace D, Nave K, Goebbels S . Neurod1 is essential for the survival and maturation of adult-born neurons. Nat Neurosci. 2009; 12(9):1090-2. PMC: 3365543. DOI: 10.1038/nn.2385. View

20.

Haigis M, Yankner B . The aging stress response. Mol Cell. 2010; 40(2):333-44. PMC: 2987618. DOI: 10.1016/j.molcel.2010.10.002. View