New research shows that cutting calories, not just the timing of meals, dramatically extends lifespan in mice, revealing key genetic influences that may help tailor future aging treatments.
Study: Dietary restriction affects health and lifespan in genetically diverse mice. Image credit: Shutterstock AI / Shutterstock.com
Deliberately 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 was published in the journal Nature investigates caloric restriction and intermittent fasting (IF) in female mice.
CR vs. DR
CR has been associated with delayed aging and prolonged lifespan. Due to the challenges of complying with CR, other forms of DR have been explored, such as time-restricted feeding or IF.
Regular fasting has been shown to be beneficial in mice despite unchanged total energy intake. The health benefits of CR can be optimized by feeding at specific times of the day, thus indicating that both caloric intake and timing of feeding influence these physiological responses.
DR affects people differently based on gender, 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 nutritional approaches to individual needs.
About the study
The researchers of the current study investigated the effects of both CR and IF on the health and lifespan of female OD (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 feeding (AL), fasting for one day (1D) or two consecutive days (2D) each week, and CR at 20% and 40% of ad libitum chow. The impact of DR on diurnal variation 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 prolonged survival in a dose-dependent manner. CR at 40% resulted in the longest 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 total intake, IF mice had longer lifespans. Aging was slowed in CR mice but not in IF mice compared to AL mice.
Energy expenditure was lowest in the 40% CR group, followed by the 20% CR and 2D IF groups. Wheel running activity decreased with age in all groups except the 40% CR group, where it increased.
DR and weight
At 40% CR, initial rapid weight loss occurred, with mice losing 24.3% of their six-month weight at 18 months with no recovery. In contrast, AL mice gained 28.4% over the same period.
All groups except the CR group at 40% gained weight by midlife, reaching 0.5–0.75% of their life cycle and losing weight rapidly towards the end of life.
Weight loss was consistently associated with reduced lifespan. Increased lean mass was associated with reduced lifespan in IF but longer lifespan in 40% of CR mice.
DR extends life span while reducing body weight and fat mass, yet maintenance of body weight and fat mass is associated with longer life span.”
Both humans and rodents show improved glucose homeostasis, reduced energy expenditure, reduced body temperature and metabolic flexibility as positive responses to DR that may be involved in their longer life span. In the current study, both body temperature and fasting glucose were reduced by DR. However, no correlation was observed between lifespan and fasting glucose, energy expenditure, or metabolic flexibility.
DR and blood cell profile
Aging-related changes in blood cells were observed, including increased proportions of B-cells, effector T-cells, and inflammatory monocytes. In comparison, the total fraction of lymphocytes, mature natural killer (NK) cells, and eosinophils decreased.
Longevity was predicted by lymphocyte counts, especially CD4+CD8+and naïve T-cells, as well as immature NK cells, which were positively associated 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.
Changes in red blood cell population, including changes in red blood cell distribution width (RDW), were observed in the 2D IF group. The inverse correlation 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 lifespan variation were inversely correlated over time, from 23.6% and 7.4% of variation at six months to 15.9% and 11.4% at 18 months, respectively.
Additional traits strongly associated with lifespan included resilience to stress, as evidenced by body weight maintained during handling periods, as well as a high lymphocyte percentage, low RDW, and increased fat mass later in life. Thus, these traits can serve as metabolism-independent biomarkers of how DR affects longevity.
Our findings suggest that improving health and extending lifespan are not synonymous and raise questions about which endpoints are most important for evaluating aging interventions in preclinical models and clinical trials.”
Journal Reference:
- Di Francesco, A., Deighan, AG, Litichevskiy, L., et al. (2024). Dietary restriction affects health and lifespan in genetically diverse mice. Nature. doi:10.1038/s41586-024-08026-3.
