Editors' ChoiceAging

“You are what you eat!”

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Science Translational Medicine  11 Mar 2020:
Vol. 12, Issue 534, eabb2771
DOI: 10.1126/scitranslmed.abb2771

Abstract

Single-cell transcriptomic analysis reveals how caloric restriction prevents aging at the cellular level.

Aging is the largest risk factor for many life-threatening diseases, including cancer, dementia, and diabetes. Although caloric restriction has previously been suggested to be one of the most effective interventions against age-related diseases, the exact cellular mechanisms underpinning its effectiveness have remained elusive.

Using single-cell and single-nucleus transcriptomic analysis performed on various tissues in rats undergoing calorie restriction, Ma et al. demonstrated that a metabolic intervention—caloric restriction—can modify the process of aging by acting through the immune system. They compared rats who ate 30% fewer calories from the age of 18 months through 27 months (comparable with a human age of 50 to 70) and looked at cells from white and brown fat, liver, kidney, aorta, skin, bone marrow, brain, and muscle. Fifty-seven percent of the age-related changes observed in tissues of aged rats on a normal diet were reversed in rats on a calorie-restricted diet.

The authors found that caloric restriction can repress age-related inflammation. Specifically, consumption of fewer calories prevented the age-dependent accumulation of plasmocytes, such as end-stage B lymphocytes in the aorta, liver, and white adipose tissue. In addition, they observed the activation of macrophages toward a pro-inflammatory (M1) stage during aging, whereas caloric restriction facilitated macrophage polarization toward an anti-inflammatory (M2) state with scavenger activity.

The study also shed light on how caloric restriction modulates key transcriptional regulatory networks. One key molecular switch, Ybx1, a master transcription factor that regulates cellular homeostasis and maintenance of stem cell population, was identified to regulate the effects of aging and caloric restriction. Correspondingly, Ybx1 was down-regulated during aging but up-regulated after caloric restriction.

Whether these effects of caloric restriction observed in rats are applicable to humans remains unclear. Nevertheless, this notion that caloric restriction can have profound effects on global immune regulation and, in turn, promote an extended healthy lifespan is intriguing. It opens new vistas for scientists to further understand aging—one of the most complex processes in biology—and may pave the way for future drug discovery efforts to promote healthy aging.

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