Active phase calorie restriction enhances longevity, UT Southwestern neuroscience study reveals

A new study in mice led by neuroscientists at UT Southwestern’s Peter O’Donnell Jr. Brain Institute shows that it’s not just calories that count.

Timing feedings to match the active period of the circadian cycle extended the life span of lab mice more than three times as much as caloric restriction alone, according to the researchers, led by Joseph Takahashi, Ph.D., Howard Hughes Medical Institute Investigator and Chair of Neuroscience, and Carla Green, Ph.D., Professor of Neuroscience. The findings are reported in Science.

“We have discovered a new facet to caloric restriction that dramatically extends life span in our lab animals,” said Dr. Takahashi, the Loyd B. Sands Distinguished Chair in Neuroscience. “If these findings hold true in people, we might want to rethink whether we really want that midnight snack.” 

Their findings show:

• Mice that ate as much and whenever they wanted lived nearly 800 days median life span – an average period for their species
• Restricting calories but making food available around the clock extended their lives only 10% to 875 days despite restricting calories by 30-40%.
• Restricting this reduced-calorie diet to the inactive period of the circadian cycle boosted lifespan by nearly 20% to an average of 959 days.
• Offering the low-calorie diet only during the active period of the cycle extended their median life span to about 1,068 days, an increase of almost 35% over the unrestricted eaters.  

“It’s pretty clear that the timing of eating is important to get the most bang for your buck with calorie restriction,” said Dr. Takahashi, one of 26 members of National Academy of Sciences and 17 members of the National Academy of Medicine at UT Southwestern.

An important and counterintuitive aspect of these studies is that body weight was not affected by the pattern or time of eating – there were no differences in body weight among the five low-calorie groups despite the substantial differences in life span.

“This shows that at low body weight, this popular yardstick of health (body weight) is not a predictor of life span,” said Dr. Green, Distinguished Scholar in Neuroscience at UT Southwestern.  

Further investigation showed that the mice that lived the longest had significantly better metabolic health, with higher insulin sensitivity and blood sugar stability. They tended to get diseases that killed the younger mice, such as various forms of cancer, at far more advanced ages. Gene expression experiments showed fewer changes in the activity of genes associated with inflammation, metabolism and aging in the long-lived animals compared to the shorter-lived ones. 

“Our findings serve as a proof-of-principle for investigating circadian clocks as potential targets to delay aging,” said Dr. Victoria Acosta-Rodriguez, Instructor of Neuroscience at UT Southwestern and lead author on the study.

Disentangling the data

Dr. Takahashi explained that experiments dating back to the 1930s have shown that decreasing typical calorie counts by about a third extends life span as well as health span – the length of time before diseases associated with old age arise – in every species in which this phenomenon has been studied. More recent research has shown that periods of fasting and restricting eating to active hours also boost health.

However, most caloric restriction experiments to date have involved feeding lab mice – which are nocturnal – on a daytime schedule that matches their human caretakers. The UTSW team used automatic feeders to avoid that.

To disentangle the effects of caloric restriction, fasting, and timing of meals on life span and health span, the Takahashi Lab and Green Lab, along with colleagues, tracked the life span and health of six groups of mice over four years.

Drs. Green and Takahashi are members of the O’Donnell Brain Institute, which recently completed a five-year, $1 billion campaign to fuel its commitment to advance brain research and clinical care.Other UTSW researchers who contributed include Filipa Rijo-Ferreira, a former Associate in the Howard Hughes Medical Institute, Mariko Izumo, Pin Xu, and Mary Wight-Carter.

The study was funded by the Howard Hughes Medical Institute, the National Institute on Aging (R01 AG045795 and R56 AG072736), the National Institute of General Medical Sciences (R35 GM127122 and K99 GM132557), and the Milky Way Research Foundation (MWRF210823). 

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.