New study shows reducing calories as well as meal timing dramatically extends lifespan in mice, reveals important genetic influences that may help tailor future aging treatments It has become.
Research: Dietary restriction affects health and longevity in genetically diverse mice. Image credit: Shutterstock AI / Shutterstock.com
The intentional reduction of dietary energy intake while avoiding malnutrition is called calorie restriction (CR). CR is associated with increased lifespan in many animal species. However, the most effective dietary restriction (DR) method for human health remains unclear.
A study recently published in the journal Nature investigated calorie restriction and intermittent fasting (IF) in female mice.
CR vs. DR
CR is associated with delayed aging and increased lifespan. Because of the compliance challenges of CR, other forms of DR are being considered, such as time-limited feeding and IF.
Periodic fasting has been shown to be beneficial in mice, even though total energy intake remains unchanged. The health benefits of CR can be optimized by feeding at specific times of the day, indicating that both caloric intake and feeding time influence these physiological responses.
DR affects individuals differently based on gender, genetics, body composition, weight, age, and pre-existing health conditions. Despite the potential benefits of DR for longevity and healthy aging, few studies have evaluated the long-term health effects of DR and its safety and efficacy in specific patient populations. there is no. This has led many researchers to begin investigating biomarkers that could potentially predict patient response to DR and tailor dietary approaches to individual needs.
About research
Researchers in the current study investigated the effects of both CR and IF on the health and longevity of female diversity outbred (DO) mice. Notably, DO mice are genetically diverse, so results using these animal models are more generalizable across species.
A total of 960 DO mice were randomly assigned to ad libitum feeding (AL), weekly 1 day (1D) or 2 consecutive days (2D) fasting, and CR with 20% and 40% of ad libitum food intake. The effects of DR on daily variations in food consumption, energy expenditure, and wheeling activity were assessed after 5, 16, and 26 months.
Impact of DR on longevity
CR was associated with increased lifespan in a dose-dependent manner. 40% CR resulted in the average and longest lifespan of mice, followed by mice with 20% CR, 2D IF, and 1D IF. In fact, the median lifespan of the 40% CR group was 9 months longer than that of mice in the AL group.
Despite compensatory feeding, which did not change overall intake, IF mice lived longer. Compared with AL mice, aging was delayed in CR mice, but not in IF mice.
Energy consumption was lowest in the 40% CR group, followed by the 20% CR and 2D IF groups. Wheel running activity decreased and increased with age in all groups except the 40% CR group.
DR and weight
At 40% CR, initial rapid weight loss occurred, with mice losing 24.3% of their 6-month body weight by 18 months and never regained it. Conversely, AL mice increased by 28.4% over the same period.
All groups except the 40% CR group gained weight until middle age, plateaued at 0.5–0.75% of the life cycle, and rapidly lost weight toward the end of life.
Weight loss was consistently associated with shorter lifespan. Increased lean body mass was associated with decreased lifespan in IF mice, but increased lifespan in 40% of CR mice.
DR increases lifespan while reducing body weight and fat mass, whereas maintaining body weight and fat mass increases lifespan. ”
Both humans and rodents exhibit positive responses to DR with improved glucose homeostasis, decreased energy expenditure, lower body temperature, and metabolic flexibility, which may play a role in extending lifespan. there is. In the current study, DR reduced both body temperature and fasting blood glucose levels. However, no association was observed between lifespan and fasting blood 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 combined fraction of lymphocytes, mature natural killer (NK) cells, and eosinophils was decreased.
Longevity was predicted by the proportion of lymphocytes, particularly CD4+, CD8+, naive T cells, and immature NK cells, all of which were positively correlated with longevity. CD4+ and CD8+ effector T cells, as well as CD11+ memory B cells, are all considered activated or mature cells and were negatively correlated with longevity.
Changes in red blood cell population, including changes in red blood cell distribution width (RDW), were observed in the 2D IF group. The inverse association between RDW and lifespan is particularly strong, thus supporting the potential utility of this trait as a biomarker.
DR-Lifespan Association Intermediary
Genetic and dietary contributions to variation in lifespan were inversely related over time, from 23.6% and 7.4% of the difference at 6 months to 15.9% and 11.4%, respectively, at 18 months.
Other traits strongly associated with longevity include resilience to stress as indicated by weight maintenance during the handling period, high percentage of lymphocytes, low RDW, and increased fat mass later in life. . Therefore, these characteristics may serve as metabolic-independent biomarkers of how DR affects lifespan.
Our findings show that improved health and extended lifespan are not synonymous and raise the question of which endpoints are most relevant for evaluating aging interventions in preclinical models and clinical trials. I am. ”
Reference magazines:
Di Francesco, A., Deighan, A. G., Litichevskiy, et al. (2024). Dietary restriction affects the health and lifespan of genetically diverse mice. Nature. doi:10.1038/s41586-024-08026-3.
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