Identification and Application of Gene Expression Signatures Associated with Lifespan Extension.

Tyshkovskiy A, Bozaykut P, Borodinova AA, Gerashchenko MV, Ables GP, Garratt M, Khaitovich P, Clish CB, Miller RA, Gladyshev VN.

Cell Metab. 2019 Sep 3;30(3):573-593.e8. doi: 10.1016/j

PMID: 31353263 

Several pharmacological, dietary, and genetic interventions that increase mammalian lifespan are known, but general principles of lifespan extension remain unclear. Here, we performed RNA sequencing (RNA-seq) analyses of mice subjected to 8 longevity interventions. We discovered a feminizing effect associated with growth hormone regulation and diminution of sex-related differences. Expanding this analysis to 17 interventions with public data, we observed that many interventions induced similar gene expression changes. We identified hepatic gene signatures associated with lifespan extension across interventions, including upregulation of oxidative phosphorylation and drug metabolism, and showed that perturbed pathways may be shared across tissues. We further applied the discovered longevity signatures to identify new lifespan-extending candidates, such as chronic hypoxia, KU-0063794, and ascorbyl-palmitate. Finally, we developed GENtervention, an app that visualizes associations between gene expression changes and longevity. Overall, this study describes general and specific transcriptomic programs of lifespan extension in mice and provides tools to discover new interventions.

https://www.ncbi.nlm.nih.gov/pubmed/31353263

The dietary switch that may boost longevity and its correlation to SAAR

The dietary switch that may boost longevity and its correlation to SAAR

A new epidemiological study published in The BMJ explores the association between eating red meat and the risk of death, specifically how risk of death can be lessened through dietary change—decreasing red meat consumption while increasing intake of healthier animal and plant-based foods. This correlates with OFAS research in rodents demonstrating that a sulfur amino acid-restricted (SAAR) diet can increase lifespan and delay onset of age-related diseases. In general, meat and other animal-based food sources have high SAA while plant-based food sources such as vegetables, legumes, whole grains, and fruits have low SAA.

The study looked to produce evidence backing previous studies showing “that higher red meat consumption, especially processed red meat, is associated with an increased risk of type 2 diabetes, cardiovascular disease, certain types of cancer, including colorectal cancer, and mortality.” Analyzing data from a cohort of 81,469 US health professionals (male and female) from a 16-year period, this study found 1) increases in red meat consumption, especially processed meat, are associated with a higher risk of death and 2) decreases in red meat consumption and simultaneous increases in healthy alternative food choices over time are associated with a lower mortality risk, further supporting the health benefits of replacing red and processed meat with healthy protein sources, whole grains, or vegetables.

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Zheng Yan, Li Yanping, Satija Ambika, Pan An, Sotos Prieto Mercedes, Rimm Eric et al. Association of changes in red meat consumption with total and cause specific mortality among US women and men: two prospective cohort studiesBMJ 2019; 365 :l2110

Researchers Find Reversible Cause of Vascular Aging

Researchers Find Reversible Cause of Vascular Aging

The hallmarks of aging in skeletal muscle include endothelial cell dysfunction, impaired microcapillary formation, and a progressive decline in exercise capacity, yet the underlying causes of these symptoms are poorly understood. In a recent paper, researchers identify the mechanism behind vascular aging in mice and its effects on muscle health, and show the means by which they successfully reversed the process in animals.

The vascular aging process causes us to suffer from disorders such as cardiac and neurologic conditions, muscle loss, impaired wound healing, and overall frailty. As we age, our tiniest blood vessels wither and die, causing reduced blood flow and compromised oxygenation of organs and tissues. Endothelial cells are essential for the health and growth of the blood vessels that they line. Unfortunately, as these endothelial cells age, blood vessels deteriorate, new blood vessels fail to form, and blood flow to most parts of the body gradually diminishes. This process heavily affects the muscles, which are vascularized and rely on a robust blood supply to function. Exercise can slow the process, but over time, it becomes less effective.

The research team found that reduced blood flow develops as endothelial cells start to lose a critical protein known as SIRT1, which has been known to delay aging and extend life in yeast and mice. SIRT1 loss is precipitated by the loss of NAD+, a key regulator of protein interactions and DNA repair. Through a series of experiments, researchers found that NAD+ and SIRT1 provide a signaling network between endothelial cells in the walls of blood vessels and muscle cells, thus generating new capillaries to supply oxygen and nutrients to tissues and organs. By using an NAD+ precursor treatment in aging mice, the scientists saw a boost in the number of blood capillaries and capillary density, increasing the blood flow to muscles. These findings have implications for improving blood flow, increasing human performance, and reestablishing a cycle of mobility in the elderly, paving the way for therapies to address diseases that arise from vascular aging.

Can Drugs Delay the Onset of Age-Related Diseases?

Can Drugs Delay the Onset of Age-Related Diseases?

Over the past ten years, understanding of the physiological changes that occur as people age has greatly improved. Common mechanisms seem to support several age-related diseases, including diabetes, Parkinson’s disease and Alzheimer’s. A review of more than 400 studies of people and animal models indicates that similar processes are the basis of DNA damage, cellular senescence, or inflammation and autophagy. Over the years, studies have shown that one age-related disease can accelerate the onset of others. Until now, aging research has focused mainly on single diseases or on delaying death, meaning that the fundamental mechanisms of aging are being missed as targets for the treatment or prevention of several age-related conditions. What’s more, patients multiple diseases are being exposed to many drugs at once, often with adverse effects.

A class of drugs called geroprotectors might be able to delay the onset of concurrent age-related diseases (multimorbidity) and boost resilience. In various animal models, these drugs can ward off problems of the heart, muscles, immune system and more. However, there are various factors, such as agreeance on definitions and desired metrics, preventing these drugs from reaching the clinic. With an ever-increasing aging population and the social and health-care systems of many nations close to a crisis point, we must take a different approach. Proof-of-concept clinical studies could demonstrate the value of geroprotectors as boosters of resilience in frail patients within the next decade. If successful, such studies could catalyze efforts to advance definitions, animal models, and the characterization of measurable outcomes against which to test the drugs.

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Sulfur amino acid restriction–induced changes in redox-sensitive proteins are associated with slow protein synthesis rates

Sulfur amino acid restriction–induced changes in redox-sensitive proteins are associated with slow protein synthesis rates

Optimal maintenance of protein quality is critical for proper cellular functions. Protein turnover (PT) is a critical contributor to protein integrity and serves other functions, such as providing amino acids during starvation or dietary deficiency. By controlling the rates of synthesis and degradation of specific proteins, PT can also help regulate a number of physiological processes, including inflammation, immunity, cholesterol metabolism, and gene transcription. Thus, a decline in PT results not just in the accumulation of damaged and nonfunctional proteins but also has wider implications for overall healthspan and lifespan.

The mechanisms underlying lifespan extension by sulfur amino acid restriction (SAAR) are still unclear. Caloric restriction and SAAR are the two dietary interventions that have shown to extend lifespan in rodent models. A significant number of mechanistic studies suggest that caloric restriction increases PT by increasing autophagy and proteasomal functions. However, some recent studies in C. elegans suggest that lower rates of protein synthesis are associated with lifespan extension. Depending on the biological context, both an increase and a decrease in protein synthesis rates could lead to increased protein quality and contribute to lifespan extension. An increase in protein synthesis would result in less damage under conditions of oxidative stress, but would also cause energy usage. Slower protein synthesis, as a result of SAAR, would lead to a decrease of energy usage. This saved energy could then be used for other cellular functions.

Restriction of protein synthesis not only minimizes cell senescence but also increases the resistance to environmental damage, including UV radiation, oxidative stress, and starvation. These advantages, when coupled with reduced oxidative insult, as shown in previous studies, might lead to a significant improvement in hepatic proteostasis. Additional studies are required to confirm whether slower rates of protein synthesis result in improved proteostasis and whether it is a contributing factor in SAAR-induced lifespan extension.