Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Stress

Area of Science:

• Gerontology
• Stem Cell Biology
• Chronobiology

Background:

• Adult stem cells exhibit daily rhythmic functions crucial for homeostasis.
• These rhythms are presumed to become arrhythmic with aging.
• Aging is associated with altered stem cell function and tissue repair capacity.

Purpose of the Study:

• To investigate the circadian clock function and transcriptional patterns in aged stem cells.
• To determine whether aging leads to arrhythmia or a reprogramming of circadian rhythms in stem cells.
• To explore the impact of diet and caloric restriction on age-related circadian changes in stem cells.

Main Methods:

• Analysis of behavioral circadian rhythms in aged mice.
• Assessment of core circadian machinery in epidermal and muscle stem cells from aged mice.
• Transcriptomic profiling of aged stem cells to identify changes in oscillating genes.
• Genetic manipulation of circadian clock components.
• Dietary interventions including high-fat diet and caloric restriction in young and aged mice.

Main Results:

• Aged mice maintain behavioral circadian rhythms.
• Stem cells in aged mice retain a functional core circadian machinery.
• The oscillating transcriptome in aged stem cells is reprogrammed, shifting from homeostasis to stress-response genes (e.g., DNA damage, autophagy).
• Circadian clock component deletion did not mimic this age-associated reprogramming.
• Caloric restriction, but not a high-fat diet, prevented transcriptome reprogramming in aged stem cells.

Conclusions:

• Stem cell circadian rhythms are reprogrammed, not lost, during aging.
• This rewiring shifts diurnal gene expression towards stress adaptation.
• Metabolic cues and age-related traits influence stem cell diurnal functions.
• Caloric restriction may mitigate age-associated circadian dysregulation in stem cells.