In pursuit of healthy aging
Harvard study shows how intermittent fasting and manipulating mitochondrial networks may increase lifespan.
Manipulating mitochondrial networks inside cells — either by dietary restriction or by genetic manipulation that mimics it — may increase lifespan and promote health, according to new research from Harvard T.H. Chan School of Public Health.
The study, published Oct. 26 online in Cell Metabolism, sheds light on the basic biology involved in cells’ declining ability to process energy over time, which leads to aging and age-related disease, and how interventions such as periods of fasting might promote healthy aging.
Mitochondria — the energy-producing structures in cells — exist in networks that dynamically change shape according to energy demand. Their capacity to do so declines with age, but the impact this has on metabolism and cellular function was previously unclear. In this study, the researchers showed a causal link between dynamic changes in the shapes of mitochondrial networks and longevity.
The scientists used C. elegans (nematode worms), which live just two weeks and thus enable the study of aging in real time in the lab. Mitochondrial networks inside cells typically toggle between fused and fragmented states. The researchers found that restricting the worms’ diet, or mimicking dietary restriction through genetic manipulation of an energy-sensing protein called AMP-activated protein kinase (AMPK), maintained the mitochondrial networks in a fused or “youthful” state. In addition, they found that these youthful networks increased lifespan by communicating with organelles called peroxisomes to modulate fat metabolism.
“Lower-energy conditions such as dietary restriction and intermittent fasting have previously been shown to promote healthy aging. Understanding why this is the case is a crucial step toward being able to harness the benefits therapeutically,” said Heather Weir, lead author of the study, who conducted the research while at Harvard Chan School and is now a research associate at Astex Pharmaceuticals. “Our findings open up new avenues in the search for therapeutic strategies that will reduce our likelihood of developing age-related diseases as we get older.”
“Although previous work has shown how intermittent fasting can slow aging, we are only beginning to understand the underlying biology,” said William Mair, associate professor of genetics and complex diseases at Harvard Chan School and senior author of the study. “Our work shows how crucial the plasticity of mitochondria networks is for the benefits of fasting. If we lock mitochondria in one state, we completely block the effects of fasting or dietary restriction on longevity.”
Next steps for the researchers including testing the role mitochondrial networks have in the effect of fasting in mammals, and whether defects in mitochondrial flexibility might explain the association between obesity and increased risk for age-related diseases.
Take Home Message:
Fasting leads to improved health because it influences on circadian rhythms and acts as a metabolic kick start.
In addition, intermittent fasting regimens may have positive effects on the gut microbiome, which has its own circadian rhythm.
Weight loss can result not only from calorie restriction but also from a temporary increase in resting energy expenditure (REE).
During a fasting period, fatty acids are released from fat cells and enter the liver, where they're converted to ketone bodies (beta-hydroxybutyrate and acetoacetate), which provide an energy source for muscles and neurons. These ketone bodies protect neurons and fuel the brain.
There's also evidence that fasting can enhance the ability of cells to remove damaged proteins and organelles through a process called Autophagy.
Time-restricted feeding (TRF) is a form of intermittent fasting that involves having a longer daily fasting period. Preliminary studies report that TRF improves cardiometabolic health in rodents and humans. Here, we performed the first study to determine how TRF affects gene expression, circulating hormones, and diurnal patterns in cardiometabolic risk factors in humans. Eleven overweight adults participated in a 4-day randomized crossover study where they ate between 8 am and 2 pm (early TRF (eTRF)) and between 8 am and 8 pm (control schedule). Participants underwent continuous glucose monitoring, and blood was drawn to assess cardiometabolic risk factors, hormones, and gene expression in whole blood cells. Relative to the control schedule, eTRF decreased mean 24-hour glucose levels by 4 ± 1 mg/dl (p = 0.0003) and glycemic excursions by 12 ± 3 mg/dl (p = 0.001). In the morning before breakfast, eTRF increased ketones, cholesterol, and the expression of the stress response and aging gene SIRT1 and the autophagy gene LC3A (all p < 0.04), while in the evening, it tended to increase brain-derived neurotropic factor (BNDF; p = 0.10) and also increased the expression of MTOR (p = 0.007), a major nutrient-sensing protein that regulates cell growth. eTRF also altered the diurnal patterns in cortisol and the expression of several circadian clock genes (p < 0.05). eTRF improves 24-hour glucose levels, alters lipid metabolism and circadian clock gene expression, and may also increase autophagy and have anti-aging effects in humans.
Ketogenic diet promotes autophagy: ketone generation requires autophagy.