Dietary Restrictions and Nutrition in the Prevention and Treatment of Cardiovascular Disease

Brandhorst and Longo, Circ Res. 2019 Mar 15;124(6):952-965

Cardiovascular disease (CVD) is the leading cause of death in many developed countries and remains one of the major diseases strongly affected by the diet. Nutrition can affect CVD directly by contributing to the accumulation of vascular plaques and also indirectly by regulating the rate of aging.

This review summarizes research on nutrition and CVD incidence based on a multipillar system that includes basic research focused on aging, epidemiological studies, clinical studies, and studies of centenarians. The relevant research linking nutrition and CVD with focus on macronutrients and aging will be highlighted.

We will review some of the most relevant studies on nutrition and CVD treatment, also focusing on interventions known to delay aging. We will discuss both everyday dietary compositions, as well as intermittent and periodic fasting interventions with the potential to prevent and treat CVD.

Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal Regeneration to Reduce Inflammatory Bowel Disease Pathology

Priya Rangan, Inyoung Choi, Min Wei, Valter D. Longo, 2019, Cell Reports 26, 2704–2719

Rangan et al. show that cycles of a fasting-mimicking diet (FMD) ameliorate intestinal inflammation, promote intestinal regeneration, and stimulate the growth of protective gut microbial populations in a mouse model displaying symptoms and pathology associated with IBD. They also show that a similar FMD is safe, feasible, and effective in reducing systemic inflammation and the consequent high levels of immune cells in humans.

Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan

Valter D. Longo and Satchidananda Panda, Perspective – Cell Metabolism, 23, June 14, 2016

Most animals alternate periods of feeding with periods of fasting often coinciding with sleep. Upon >24 hr of fasting, humans, rodents, and other mammals enter alternative metabolic phases, which rely less on glucose and more on ketone body-like carbon sources.

Both intermittent and periodic fasting result in benefits ranging from the prevention to the enhanced treatment of diseases. Similarly, time-restricted feeding (TRF), in which food consumption is restricted to certain hours of the day, allows the daily fasting period to last >12 hr, thus imparting pleiotropic benefits.

Understanding the mechanistic link between nutrients and the fasting benefits is leading to the identification of fasting-mimicking diets (FMDs) that achieve changes similar to those caused by fasting. Given the pleiotropic and sustained benefits of TRF and FMDs, both basic science and translational research are warranted to develop fasting-associated interven-tions into feasible, effective, and inexpensive treatments with the potential to improve healthspan

Fasting and cancer: molecular mechanisms and clinical application

Alessio Nencioni, Irene Caffa, Salvatore Cortellino and Valter D. Longo
Nature Reviews – Cancer volume 18, November 2018

The vulnerability of cancer cells to nutrient deprivation and their dependency on specific metabolites are emerging hallmarks of cancer.

Fasting or fasting- mimicking diets (FMDs) lead to wide alterations in growth factors and in metabolite levels, generating environments that can reduce the capability of cancer cells to adapt and survive and thus improving the effects of cancer therapies.

In addition, fasting or FMDs increase resistance to chemotherapy in normal but not cancer cells and promote regeneration in normal tissues, which could help prevent detrimental and potentially life- threatening side effects of treatments.

While fasting is hardly tolerated by patients, both animal and clinical studies show that cycles of low- calorie FMDs are feasible and overall safe.

Several clinical trials evaluating the effect of fasting or FMDs on treatment- emergent adverse events and on efficacy outcomes are ongoing.

We propose that the combination of FMDs with chemotherapy , immunotherapy or other treatments represents a potentially promising strategy to increase treatment efficacy , prevent resistance acquisition and reduce side effects.

Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans

Yen et al. SCIENTIFIC REPORTS | (2018) 8:14212

Advanced age is associated with a decline in cognitive function, likely caused by a combination of modifiable and non-modifiable factors such as genetics and lifestyle choices.

Mounting evidence suggests that humanin and other mitochondrial derived peptides play a role in several age-related conditions including neurodegenerative disease. Here we demonstrate that humanin administration has neuroprotective effects in vitro in human cell culture models and is sufficient to improve cognition in vivo in aged mice.

Furthermore, in a human cohort, using mitochondrial GWAS, we identified a specific SNP (rs2854128) in the humanin-coding region of the mitochondrial genome that is associated with a decrease in circulating humanin levels.

In a large, independent cohort, consisting of a nationally-representative sample of older adults, we find that this SNP is associated with accelerated cognitive aging, supporting the concept that humanin is an important factor in cognitive aging.

Starvation, Stress Resistance, and Cancer

Roberta Buono and Valter D. Longo, Trends in Endocrinology & Metabolism, April 2018, Vol. 29, No. 4

Cancer cells are characterized by dysregulation in signal transduction and metabolic pathways leading to increased glucose uptake, altered mitochon-drial function, and the evasion of antigrowth signals.

Fasting and fasting-mimicking diets (FMDs) provide a particularly promising intervention to pro-mote differential effects in normal and malignant cells.

These effects are caused in part by the reduction in IGF-1, insulin, and glucose and the increase in IGFBP1 and ketone bodies, which generate conditions that force cancer cells to rely more on metabolites and factors that are limited in the blood, thus resulting in cell death.

Here we discuss the cellular and animal experiments demonstrating the differential effects of fasting on normal and cancer cells and the mechanisms responsible for these effects.

Periodic fasting starves cisplatin-resistant cancers to death

Novella Guidi & Valter D Longo, The EMBO Journal 37:e99815 | 2018

Treatment of cancers with the cytotoxic agent cisplatin frequently evokes resis-tance, accompanied by rewiring of meta-bolic pathways, limiting its clinical use.

Recent research by Obrist et al (2018) shows that cisplatin-resistant growth of lung adenocarcinoma is particularly vulnerable to periodic fasting cycles and starvation-induced cell death, due to its dependency on glutamine, required for nucleoside biosynthesis, suggesting an opportunity for nutritional anti-cancer interventions.

Programmed longevity, youthspan, and juventology

Valter Longo

The identification of conserved genes and pathways that regulate lifespan but also healthspan has resulted in an improved understanding of the link between nutrients, signal transduction proteins, and aging but has also provided evidence for the exis-
tence of multiple “longevity programs,” which are selected based on the availability of nutrients.

Periodic fasting and other dietary restrictions can promote entry into a long‐lasting longevity program characterized by cellular protection and optimal func-tion but can also activate regenerative processes that lead to rejuvenation, which are independent of the aging rate preceding the restricted period.

Thus, a “juventol-ogy”‐based strategy can complement the traditional gerontology approach by focus-ing not on aging but on the longevity program affecting the life history period in which mortality is very low and organisms remain youthful, healthy, and fully func-tional.

Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease

Min Wei, Sebastian Brandhorst et al. Sci. Transl. Med. 9, eaai8700 (2017) 15 February 2017

Calorie restriction or changes in dietary composition can enhance healthy aging, but the inability of most subjects to adhere to chronic and extreme diets, as well as potentially adverse effects, limits their application.

We randomized 100 generally healthy participants from the United States into two study arms and tested the effects of a fasting-mimicking diet (FMD)—low in calories, sugars, and protein but high in unsaturated fats—on markers/risk factors associated with aging and age-related diseases.

We compared subjects who followed 3 months of an unrestricted diet to subjects who consumed the FMD for 5 consecutive days per month for 3 months.

Three FMD cycles reduced body weight, trunk, and total body fat; lowered blood pressure; and decreased insulin-like growth factor 1 (IGF-1). No serious adverse effects were reported. After 3 months, control diet subjects were crossed over to the FMD program, resulting in a total of 71 subjects completing three FMD cycles.

A post hoc analysis of subjects from both FMD arms showed that body mass index, blood pressure, fasting glucose, IGF-1, triglycerides, total and low-density lipoprotein cholesterol, and C-reactive protein were more beneficially affected in participants at risk for disease than in subjects who were not at risk.

Thus, cycles of a 5-day FMD are safe, feasible, and effective in reducing markers/risk factors for aging and age-related diseases. Larger studies in patients with diagnosed dis-eases or selected on the basis of risk factors are warranted to confirm the effect of the FMD on disease prevention and treatment.

PLoS Genetics January 2008

Life Span Extension by Calorie Restriction Depends on Rim15 and Transcription Factors Downstream of Ras/PKA, Tor, and Sch9