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NIH grant 1K99AG097913-01A1: The Impact of Circadian Aligned Time-Restricted Feeding on Reproductive Rhythms and Aging
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Samantha Iiams. Award: $137460.
Start: 2026-09-11T00:00:00.
PROJECT SUMMARY/ABSTRACT
While human lifespans are increasing due to medical advances, healthspan remains limited, with many spending
≥10% of their later years suffering from cardiometabolic and neurological diseases. Aging is the primary risk
factor for these morbidities and is associated with a decline in circadian rhythms. Caloric restriction has been
shown to extend health and lifespan in model organisms. When combined with circadian aligned time-restricted
feeding (TRF), alignment of feeding with an organism’s active phase, these aging benefits are further enhanced
and are correlated with improved circadian rhythms. While TRF alone boosts circadian rhythms and health, its
potential to extend lifespan in mammals is unknown. Additionally, the effects of TRF under normal nutritional
conditions and in females are largely unexplored.
My preliminary data testing 12-hour (h) or 8h of circadian aligned TRF using normal chow, has provided insights
into its impact on aging in both male and female mice. Notably, only 8h-TRF extended lifespan in males. TRF
also conferred sex-dependent improvements in health, with females showing more prolonged health relative to
their lifespan compared to males. Illness records also showed females spent significantly less time in a frail state
before death. This suggests healthspan, rather than lifespan, is better improved in females than males. In line
with studies finding sex-differences in the circadian system, I hypothesize that sex-specific differences in
circadian regulation differentially influences healthspan.
Impacts to female reproductive clocks may underlie these healthspan disparities, as estrogen, which is clock-
controlled, positively influences circadian rhythms and protects against diseases. My goal is to elucidate how
TRF impacts pathways that regulate reproductive rhythms and function. In Aim 1, I will test the hypothesis that
TRF mitigates age-related changes in the overall level and 24h patterns of expression of receptors and gene
outputs involved in FGF21 hypothalamic signaling, a factor induced by TRF and linked in regulating reproduction.
In Aim 2, I will test if TRF rescues age-related declines in level and 24h expression patterns of hypothalamic
Kiss1 and GnRH, which indirectly signal to the ovarian clock. I will also test in an unbiased manner which genes
and cell-types within the ovary are impacted by aging and TRF. In Aim 3, I will functionally test if circadian
enhancement via TRF, or transgenic overexpression of CLOCK impacts female reproductive function with age
through measurements of sex hormones, estrous cycling, follicle counts, and fertility index. I will also correlate
these reproductive markers with systemic health to determine if reproductive aging is linked to overall aging.
Using single-nucleus RNA-Sequencing, histology, immunoassays, and in vivo physiological and behavioral
assays, this study will reveal whether circadian interventions enhance reproductive longevity.document fetched 2026-09-20 02:42