Concerted enhancement of core and output rhythms to promote healthy aging

PROJECT SUMMARY / ABSTRACT
The 24/7 lifestyle in modern society disrupts natural circadian rhythms and poses a serious health concern.
Epidemiological and laboratory evidence indicates that circadian disturbances adversely affect various biological
functions and increase disease risk. The circadian clock, a network of cellular oscillators, is the biological timer
driving output gene expression and physiological functions with ~24h rhythmicity. During aging, the clock and
clock-controlled rhythms display attenuated oscillatory amplitude, concomitant with physiological and behavioral
decline. Importantly, environmental/dietary interventions support a positive modifiable function of the clock to
promote healthy aging. For example, several dietary interventions that prolong healthy lifespan and/or longevity,
including caloric restriction and time-restricted feeding in the active phase (TRF), were found to enhance
circadian gene oscillation and output metabolism. Together with genetic evidence, these observations strongly
suggest a crucial regulatory role of robust circadian oscillation in healthy aging. We previously identified Nobiletin
(NOB), a polymethoxylated dietary flavonoid, as a clock-enhancing compound. We found that NOB activates
RORs (specifically the alpha and gamma subtypes, encoded by Rora and Rorc), key components of the cellular
oscillator, to elevate circadian amplitude and improve energy homeostasis in metabolic disease mice.
Importantly, in naturally aged mice, we recently showed that the NOB-ROR axis strengthens metabolic
homeostasis and promotes energy expenditure in part via mitochondrial activation in skeletal muscle, ultimately
bolstering healthy aging and survival. Therefore, NOB (a dietary flavonoid) and TRF differentially modify
circadian core oscillator and feeding rhythms, performing overlapping functions to improve fitness during aging.
In this proposal, we hypothesize that NOB and TRF synergistically enhance core oscillators and output rhythms
to maintain a robust clock and promote healthy aging, via mechanisms impinging on molecular oscillators and
mitochondrial function. In Aim 1, building on our strong preliminary studies, we will determine roles of ad libitum
NOB treatment in single-cell oscillators and transcriptional/epigenetic regulation to enhance circadian amplitude
in aged mice. In Aim 2, we will determine function and mechanism of an integrated NOB.TRF regiment to
coordinately activate circadian rhythms and physiology in aged mice in a concerted manner. In Aim 3, we will
delineate the circadian mechanisms via which NOB and TRF regulate mitochondrial respiration. Together, the
proposed studies will provide key mechanistic insights into the role of circadian rhythms during aging, and
pinpoint an integrated dietary regimen as a novel strategy to activate clocks and extend healthspan. The
innovations include a dual-component dietary regimen coordinately enhance clock amplitude for healthy aging
and a novel circadian regulation of mitochondrial respiratory complex architecture and cardiolipin synthesis.
Given the pressing lifestyle-related health challenges, our study may ultimately facilitate implementation of an
efficacious dietary intervention to improve quality of life at old ages through robust circadian timing.

Grant Number: 5R01AG065984-05
NIH Institute/Center: NIH
Principal Investigator: Zheng Chen