Locations:
Search IconSearch

Fasting Reduces Frailty and Extends Healthspan in Late-Life Preclinical Models

Research shows improvement in metabolic, muscular and cognitive fitness

21-GER-2214260_CQD_650x450_12884503

Dietary restriction initiated in late life has been shown to reduce aging-related frailty and extend healthspan, according to a preclinical study by Cleveland Clinic researchers.

Advertisement

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

“Although life expectancy has increased, people are not necessarily living that entire time in good health,” notes Christopher Hine, PhD, a researcher in the Department of Cardiovascular & Metabolic Sciences in Cleveland Clinic’s Lerner Research Institute.

There is a growing body of evidence that among animal models, dietary restriction enhances health and increases lifespan. These benefits have not been fully realized in patients, however, because compliance to strict dietary regimens is more difficult in people.

In a study published in Geroscience, Dr. Hine and his team tested a more clinically applicable regimen in mice. The study was funded in part by the National Institute on Aging (NIA) and the National Heart, Lung, and Blood Institute (NHLBI).

“In clinical practice, even the most effective therapeutic interventions only work if patients adhere to them,” says Dr. Hine. “We believe that every-other-day (EOD) fasting is more attainable than daily dietary restriction. We have yet to test this intervention in patients, but are optimistic about the positive findings in preclinical models.”

Benefits of every-other-day fasting seen in male mice

The researchers compared the effects of two dietary regimens on several indicators of frailty, which researchers that study aging have found to be a more accurate predictor of mortality than chronological age. Beginning in late life, groups had either unrestricted access to a standard diet every day or cycled between days of fasting and unrestricted access to the same standard diet.

Dr. Hine and his team found that the benefits of EOD fasting were primarily seen in male mice. EOD fasting reduced overall energy intake, body weight and fat mass. It also enhanced several indicators of frailty, including metabolic fitness, muscular functions and some cognitive functions.

Advertisement

According to Dr. Hine, cognitive performance has not been widely tested in other preclinical studies related to dietary restriction and aging.

“We found that late-life initiated EOD fasting led to improved performance on two cognitive tests related to hippocampus-dependent memory — the type of memory involved in spatial memory and consolidating short-term memory to long-term memory,” he says.

Alzheimer’s disease and other dementias are typically related to age. Additional research is necessary, but these findings offer important insights into dietary intervention as a potential approach to improve healthspan and prevent cognitive impairment in patients.

A possible source for the sex-based differences in healthspan benefits

Looking for a biological explanation as to why primarily only male mice experienced these health benefits, the researchers found that female mice, but not male mice, overcompensated their food intake on the fed day. EOD fasting also increased levels of the chemical compound hydrogen sulfide in the kidneys of males but not females. Previous research has shown that aging decreases expression and activity of the enzymes that produce the compound.

The findings show that among male mice, higher hydrogen sulfide levels were associated with the greatest improvements in age-related frailty, suggesting the sex-based differences may be modulated in part by the compound’s production. Dr. Hine and his team recently published findings in Nature Communications from a companion study, also funded by the NIA and NHLBI, that took a closer look at the molecular changes caused by EOD fasting and caloric restriction.

Advertisement

Dietary restriction alters hydrogen sulfide levels

Hydrogen sulfide is involved in many critical biochemical reactions in the body and sends signals through a process called protein persulfidation. According to Dr. Hine, persulfidated proteins have an altered chemical structure that is easy to recognize.

“We measured the levels of persulfidated proteins in various tissues throughout our EOD fasting preclinical models and compared expression levels with models fed an unrestricted diet,” he explains.

Like their earlier findings, the researchers showed that dietary restriction increased levels of hydrogen sulfide. They also found EOD fasting increased levels of an enzyme involved in hydrogen sulfide production (called cystathionine γ-lyase).

Protein persulfidation was enriched in several organs — including the liver, kidney, muscle and brain — of both young and old mice under EOD fasting and caloric restriction, and particularly abundant in cellular pathways known to be involved in metabolic health and aging. Mice lacking the enzyme that produces hydrogen sulfide had significantly reduced levels of persulfidated proteins, which were not rescued even following dietary restriction.

Taken together, the team’s findings suggest that dietary restriction increases production capacity of hydrogen sulfide, which is suspected to confer metabolic and aging-related benefits. The researchers’ next steps will be to investigate the specific downstream effects of protein persulfidation and if they can be targeted, opening the door for both dietary and therapeutic interventions to prevent aging-related decline and extend lifespan.

Advertisement

Related Articles

Medical graphic depicting CD55 movement to cell nucleus
Nuclear CD55 Fuels Platinum Resistance in Ovarian Cancer

Researchers identify potential path to retaining chemo sensitivity

gut microbes in intestine
Cleveland Clinic, Tufts University Research Ties Gut Microbial TMAO Pathway to Chronic Kidney Disease

Large-scale joint study links elevated TMAO blood levels and chronic kidney disease risk over time

patient in ICU
Cleveland Clinic and Purdue Seek to Revolutionize Intensive Care Through AI

Investigators are developing a deep learning model to predict health outcomes in ICUs.

24-NEU-4528160-genetics-parkinson-disease-650×450
Multi-Ancestry Genetic Study of Parkinson’s Disease Identifies New Risk Genes in Pursuit of Novel Treatment Targets

International collaboration is most genetically diverse study of the disease to date

23-NEU-4357266-stock-brain-image_650x450
Noninvasive Technology Enhances Ability to Map Brain Activity to Track Behavior Change

Preclinical work promises large-scale data with minimal bias to inform development of clinical tests

Hydrogen sulfide
Can Boosting Hydrogen Sulfide Bolster Standard-of-Care Glioblastoma Therapy to Extend Survival?

Cleveland Clinic researchers pursue answers on basic science and clinical fronts

23-NEU-4390509-CQD-Hero-650×450
Microglial Immunometabolism Endophenotypes Implicated in Sex Differences in Alzheimer’s Disease

Study suggests sex-specific pathways show potential for sex-specific therapeutic approaches

23-CCC-4375928 Quantum Innovation Catalyzer 650×450
A Unique Opportunity to Explore Quantum Computing’s Potential

Cleveland Clinic launches Quantum Innovation Catalyzer Program to help start-up companies access advanced research technology

Ad