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Caloric Restriction and Lifespan Extension in Mice

Review of recent research on the impact of caloric restriction (CR) and intermittent fasting (IF) on lifespan and health in genetically diverse mice.

• CR and IF extend lifespan in mice: Both CR and IF, implemented in varying degrees, resulted in lifespan extension proportional to the level of restriction. 40% CR had the strongest effect, increasing median lifespan by 36.3%. Notably, IF also extended lifespan despite minimal or no reduction in total caloric intake.

• Genetic influence is stronger than diet: While diet impacted lifespan, genetic background had a larger influence, explaining 23.6% of lifespan variation compared to 7.4% explained by diet. This genetic influence decreased with age while the impact of diet increased.

• Resilience is key: Mice that maintained body weight despite stress and CR lived longest, suggesting resilience is a crucial factor for longevity. "Our study really points to the importance of resilience,” states Gary Churchill, PhD, the study's senior author. "The most robust animals keep their weight on even in the face of stress and caloric restriction, and they are the ones that live the longest.”

• Health and lifespan are not synonymous: While some health markers improved with DR, they were surprisingly poor predictors of lifespan. Metabolic improvements like reduced adiposity and lower fasting glucose were not directly linked to increased lifespan. This challenges the assumption that DR primarily benefits longevity by counteracting obesity's negative effects.

• Specific traits linked to longevity: Retention of body weight during periods of stress, high lymphocyte proportion, low red blood cell distribution width (RDW), and high adiposity in late life were strongly associated with longer lifespan.

• Potential downsides of CR: 40% CR, while extending lifespan most effectively, also led to lean mass loss and immune repertoire changes that could increase infection susceptibility.

• Limitations of IF: IF was less effective in mice with high pre-intervention body weight, and two-day IF was associated with erythroid cell population disruption.

Important Considerations:

• The study involved only female mice. Further research is needed to determine if the findings apply to males.

• Current human longevity studies often focus on metabolic markers, which this research suggests might be less relevant than other factors like immune health and RDW.

Quotes:

• "Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials." - Di Francesco, et al. (2024)

• "If you want to live a long time, there are things you can control within your lifetime such as diet, but really what you want is a very old grandmother." - Gary Churchill, PhD (Neuroscience News, 2024)

Implications:

• This research suggests that personalized approaches to DR, considering individual genetics and health status, are needed to maximize benefits and minimize risks.

• Future research should focus on identifying reliable biomarkers for predicting individual responses to DR.

• The findings challenge the traditional understanding of how DR extends lifespan and highlight the importance of resilience and specific physiological traits beyond metabolic health.

Further Research:

• Investigating the specific genetic mechanisms influencing lifespan and responses to DR.

• Examining the impact of CR and IF on lifespan and health in male mice.

• Exploring the long-term effects of different DR regimens on the immune system and susceptibility to infections.

• Developing personalized DR strategies based on individual genetic and physiological profiles.