Caloric restriction extends mouse lifespan and health in new genetic study.

New research shows that cutting calories, not just meal timing, dramatically extends lifespan in mice, uncovering key genetic influences that may help tailor future aging therapies.

Intentionally reducing dietary energy intake while avoiding malnutrition is referred to as caloric restriction (CR). CR is associated with increased longevity in many animal species; however, the most effective form of dietary restriction (DR) for human health remains unclear.

A recent study published I the journaln Nature explores caloric restriction and intermittent fasting (IF) in female mice.

CR vs. DR

CR has been associated with delayed aging and extended lifespan. Due to compliance challenges with CR, other forms of DR, such as time-restricted feeding or IF, have been explored.

Regular fasting has been shown to be beneficial in mice despite unchanged overall energy intake. The health benefits of CR can be optimized by feeding at specific times of day, thus indicating that both caloric intake and feeding time influence these physiological responses.

DR affects individuals differently based on their sex, genetics, body composition, weight, age, and existing health conditions. Despite the potential benefits of DR on lifespan and healthy aging, few studies to date have evaluated the long-term health effects of DR and its safety and efficacy for certain patient populations. This has led many researchers to begin investigating potential biomarkers that could predict patient responses to DR and tailor these dietary approaches to individual needs.

About the study

The current study's researchers investigated the effects of both CR and IF on the health and lifespan of female diversity outbred (DO) mice. Notably, DO mice are genetically diverse, which allows any results using these animal models to be more generalizable across species.

A total of 960 DO mice were randomly assigned to ad libitum (AL) feeding, fasting one day (1D) or two consecutive days (2D) each week, and CR at 20% and 40% of unrestricted food intake. The impact of DR on daily fluctuations in food consumption, energy expenditure, and wheel running activity was assessed at five, 16, and 26 months.

Effects of DR on lifespan

CR was associated with extended lifespans in a dose-dependent manner. CR at 40% led to the greatest median and maximum lifespan in mice, followed by those with 20% CR, 2D IF, and 1D IF. In fact, the median lifespan in the 40% CR group was nine months longer than in mice in the AL group.

Despite compensatory feeding with unchanged overall intake, IF mice had a longer lifespan. Aging slowed in the CR mice but not in the IF mice compared to the AL mice.

Energy expenditure was lowest in the 40% CR group, followed by the 20% CR and 2D IF groups. Wheel running activity declined with age in all groups except for the 40% CR group, where it increased.

DR and weight

With 40% CR, initial rapid weight loss occurred, with mice losing 24.3% of their six-month weight by 18 months with no recovery. Conversely, AL mice gained 28.4% during the same period.

All groups except the 40% CR group gained weight until midlife, plateaued at 0.5-0.75% of their lifecycle, and lost weight rapidly towards the end of their lives.

Weight loss was consistently associated with reduced lifespan. Increased lean mass was associated with a reduced lifespan in IF but a greater lifespan in 40% of CR mice.

Both humans and rodents exhibit improved glucose homeostasis, reduced energy expenditure, reduced body temperature, and metabolic flexibility as positive responses to DR that may be involved in their longer lifespans. In the current study, both body temperature and fasting glucose declined with DR; however, no association was observed between lifespan and fasting glucose, energy expenditure, or metabolic flexibility.

DR and blood cell profiles

Aging-related changes in blood cells, including increased proportions of B-cells, effector T-cells, and inflammatory monocytes, were observed. Comparatively, the total fraction of lymphocytes, mature natural killer (NK) cells, and eosinophils were reduced.

Longevity was predicted by lymphocyte percentages, particularly those of CD4⁺, CD8⁺, and naïve T-cells, as well as immature NK cells, all of which were positively correlated with lifespan. CD4+ and CD8+ effector T-cells, as well as CD11+ memory B-cells, all of which are considered activated or mature cells, were negatively associated with lifespan.

Red cell population changes, including alterations in red cell distribution width (RDW), were observed in the 2D IF group. The inverse association between RDW and lifespan was particularly strong, thus supporting the potential utility of this trait as a biomarker.

Mediators of the DR-lifespan association

Genetic and dietary contributions to variations in lifespan were inversely related over time, from 23.6% and 7.4% of the variance at six months to 15.9% and 11.4% at 18 months, respectively.

Additional traits that were strongly associated with lifespan included resilience to stress, as demonstrated by body weight retained during periods of handling, as well as a high proportion of lymphocytes, low RDW, and increased fat mass later in life. Thus, these characteristics may serve as metabolism-independent biomarkers of how DR impacts longevity.

Journal reference:

• Di Francesco, A., Deighan, A. G., Litichevskiy, L., et al. (2024). Dietary restriction impacts health and lifespan of genetically diverse mice. Nature. doi:10.1038/s41586-024-08026-3.