Calorie restriction is the practice of eating fewer calories, as much as a 40% reduction from the usual ad libitum calorie intake, while still obtaining an adequate level of micronutrients. Various forms of intermittent fasting also act as calorie restriction; the important factor is likely the length of time spent in a state of hunger. In a variety of animal species, calorie restriction has been shown to slow aging and extend life span, as well as produce sweeping positive changes to the operation of cellular metabolism in tissues throughout the body.
Human studies of mild long-term calorie restriction have reproduced the short-term changes, but there is no data on effects on life expectancy. Researchers expect calorie restriction to produce smaller changes in long-lived species such as our own than it does in short-lived species such as mice. The reasoning here is that the calorie restriction response evolved because of seasonal famine, a way for the individuals of short-lived species to increase the odds of later reproduction in a period of relative plenty. A season is a large fraction of a mouse life span, but not of a human life span – so only short-lived species exhibit large gains in life span via calorie restriction. Further, we might expect that long-lived species become long-lived in part because some of the beneficial changes produced by calorie restriction in short-lived species become enabled by default, throughout life.
Today’s open access paper is illustrative of many similar efforts to investigate the fine details of the calorie restriction response in one specific organ. Here, the cell populations of the brain were the focus, and researchers profiled gene expression for hundreds of thousands of distinct cells in different brain regions. The results are quite interesting.
Spatiotemporal profiling reveals the impact of caloric restriction in the aging mammalian brain
Aging induces functional decline in the mammalian brain, increasing its vulnerability to cognitive impairments and neurodegenerative disorders. Among the various interventions to slow aging and delay age-related diseases, caloric restriction (CR) is particularly notable for its consistency in extending lifespan across species, including worms, flies, rats, and mice. Importantly, CR has demonstrated beneficial effects on brain function, enhancing learning and memory and increasing resilience against neurodegenerative diseases. However, established methods such as bulk transcriptomics yield little insight into how CR acts on highly heterogeneous brain cell populations and regions to mitigate the molecular and cellular changes of aging.
Recent advances in single-cell transcriptomics and spatial transcriptomics have enabled the precise measurement of gene expression changes across distinct cell populations and brain regions. However, the low throughput of standard approaches remains a challenge, impeding the study of how hundreds of different brain cell states respond to anti-aging treatments, particularly for rare yet critical aging-associated cell populations (e.g., neurogenic cells and activated microglia). To improve throughput, we recently developed two scalable approaches, EasySci and IRISeq, which enable comprehensive single-cell and spatial transcriptomic analysis of the mammalian brain across ages and conditions.
In this study, we profiled more than 500,000 cells from 36 control and CR mouse brains across three age groups with EasySci single-nucleus transcriptomics and performed imaging-free IRISeq spatial transcriptomics on twelve brain sections from CR and control aged mice. We thereby explored the impact of CR in more than 300 cellular states and 11 brain regions. CR delayed expansion of inflammatory cell populations, preserved neural precursor cells, and broadly reduced the expression of aging-associated genes involved in cellular stress, senescence, inflammation, and DNA damage. CR restored the expression of region-specific genes linked to cognitive function, myelin maintenance, and circadian rhythm. In summary, we provide a high-resolution spatiotemporal map of the aging mouse brain’s response to CR, detailing precise cellular and molecular mechanisms behind its neuroprotective effects.
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