Summary 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, four 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.

Summary Mice and humans with Growth Hormone Receptor/IGF-1 deficiencies display major reductions in age-related diseases. Because protein restriction reduces GHR-IGF-1 activity, we examined links between protein intake and mortality. Respondents (n=6,381) aged 50–65 reporting high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer and diabetes mortality during an 18 year follow up period. These associations were either abolished or attenuated if the source of proteins was plant-based. Conversely, in respondents over age 65, high protein intake was associated with reduced cancer and overall mortality. Mouse studies confirmed the effect of high protein intake and the GHR-IGF-1 axis on the incidence and progression of breast and melanoma tumors, and also the detrimental effects of a low protein diet in the very old. These results suggest that low protein intake during middle age followed by moderate protein consumption in old subjects may optimize healthspan and longevity.

Short-term starvation (or fasting) protects normal cells, mice, and potentially humans from the harmful side effects of a variety of chemotherapy drugs. Here, we show that treatment with starvation conditions sensitized yeast cells (Saccharomyces cerevisiae) expressing the oncogene-like RAS2val19 to oxidative stress and 15 of 17 mammalian cancer cell lines to chemotherapeutic agents. Cycles of starvation were as effective as chemotherapeutic agents in delaying progression of different tumors and increased the effectiveness of these drugs against melanoma, glioma, and breast cancer cells. In mouse models of neuroblastoma, fasting cycles plus chemotherapy drugs—but not either treatment alone—resulted in long-term cancer-free survival. In 4T1 breast cancer cells, short-term starvation resulted in increased phosphorylation of the stress-sensitizing Akt and S6 kinases, increased oxidative stress, caspase-3 cleavage, DNA damage, and apoptosis. These studies suggest that multiple cycles of fasting promote differential stress sensitization in a wide range of tumors and could potentially replace or augment the efficacy of certain chemotherapy drugs in the treatment of various cancers.

Strategies to treat cancer have focused primarily on the killing of tumor cells. Here, we describe a differential stress resistance (DSR) method that focuses instead on protecting the organism but not cancer cells against chemotherapy. Short-term starved S. cerevisiae or cells lacking proto-oncogene homologs were up to 1,000 times better protected against oxidative stress or chemotherapy drugs than cells expressing the oncogene homolog Ras2 val19 . Lowglucose or low-serum media also protected primary glial cells but not six different rat and human glioma and neuroblastoma cancer cell lines against hydrogen peroxide or the chemotherapy drug/ pro-oxidant cyclophosphamide. Finally, short-term starvation provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/prooxidant etoposide. These studies describe a starvation-based DSR strategy to enhance the efficacy of chemotherapy and suggest that specific agents among those that promote oxidative stress and DNA damage have the potential to maximize the differential toxicity to normal and cancer cells.reactive oxygen species ͉ short-term starvation ͉ maintenance mode O ur studies in S. cerevisiae and those of others in worms, flies, and mice have uncovered a strong association between lifespan extension and resistance to oxidative stress (1-6). This resistance is observed in long-lived yeast cells lacking RAS2 and SCH9, the orthologs of components of the human Ras and Akt/S6K pathways (2, 5, 7), and in long-lived worms and mice with reduced activity of homologs of the IGF1 receptor (IGF1R), implicated in many human cancers (8). Notably, the IGF1R functions upstream of Ras and Akt in mammalian cells (3-6). Stress resistance is also observed in model systems in which calorie intake is reduced by at least 30% (9). This reduced calorie intake, also known as calorie restriction (CR) or dietary restriction (DR), has been studied for many years and is known to extend life span in organisms ranging from yeast to mice (10). CR also protects against spontaneous cancers and against carcinogen-induced cancers (10-12), raising the possibility that CR and reduced IGF1 may increase stress resistance by similar mechanisms.Our discovery of the role of Ras2 and Sch9 in the negative regulation of antioxidant and other protective systems together with the association between mutations that activate IGF1R, Ras, or Akt and many human cancers prompted our hypothesis that normal but not cancer cells would respond to starvation or down-regulation of Ras/Akt signaling by entering a stressresistance mode. In fact, one of the major ''hallmarks of cancer cells'' is the self-sufficiency for growth signals (13). In the majority of cancers, this ability to grow or remain in a growth mode even in the absence of growth factors is provided by the hyperactivation of one or several components of the IGF1R, Ras, Akt, and mTor pathways.Here, we tested the hypothesis that short-term starvation (STS) or low glucose/low serum can protect mammalian c...