Calico Life Sciences LLC, South San Francisco, CA, USA.
The Jackson Laboratory, Bar Harbor, ME, USA.
Nature. 2024 Oct;634(8034):684-692. doi: 10.1038/s41586-024-08026-3. Epub 2024 Oct 9.
Caloric restriction extends healthy lifespan in multiple species. Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored. Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity. Here we performed an extensive assessment of graded levels of caloric restriction (20% and 40%) and intermittent fasting (1 and 2 days fasting per week) on the health and survival of 960 genetically diverse female mice. We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction. Lifespan was heritable and genetics had a larger influence on lifespan than dietary restriction. The strongest trait associations with lifespan included retention of body weight through periods of handling-an indicator of stress resilience, high lymphocyte proportion, low red blood cell distribution width and high adiposity in late life. Health effects differed between interventions and exhibited inconsistent relationships with lifespan extension. 40% caloric restriction had the strongest lifespan extension effect but led to a loss of lean mass and changes in the immune repertoire that could confer susceptibility to infections. Intermittent fasting did not extend the lifespan of mice with high pre-intervention body weight, and two-day intermittent fasting was associated with disruption of erythroid cell populations. Metabolic responses to dietary restriction, including reduced adiposity and lower fasting glucose, were not associated with increased lifespan, suggesting that dietary restriction does more than just counteract the negative effects of obesity. 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.
热量限制能延长多种物种的健康寿命。间歇性禁食是一种替代的饮食限制形式，对人类来说可能更可持续，但它的效果在很大程度上仍未得到探索。确定最有效的饮食限制形式是开发改善人类健康和长寿干预措施的关键。在这里，我们对 960 只遗传多样性的雌性小鼠进行了广泛的评估，研究了不同程度的热量限制（20%和 40%）和间歇性禁食（每周禁食 1 天和 2 天）对健康和生存的影响。结果表明，热量限制和间歇性禁食都能延长寿命，与限制的程度成正比。寿命是可遗传的，遗传对寿命的影响大于饮食限制。与寿命关联最强的特征包括在处理期间保持体重——这是一种抗压能力的指标、淋巴细胞比例高、红细胞分布宽度低和晚年肥胖程度高。干预措施之间的健康影响不同，与寿命延长的关系也不一致。40%的热量限制对延长寿命的效果最强，但会导致瘦体重的损失和免疫谱的改变，从而增加感染的易感性。间歇性禁食并不能延长干预前体重较高的小鼠的寿命，而且两天的间歇性禁食与红细胞群体的破坏有关。饮食限制引起的代谢反应，包括减少肥胖和降低空腹血糖，与寿命延长无关，这表明饮食限制不仅仅是抵消肥胖的负面影响。我们的研究结果表明，改善健康和延长寿命并不等同，这引发了关于在临床前模型和临床试验中评估衰老干预措施时哪些终点最相关的问题。
