Importance of circadian timing for aging and longevity

Abstract

Dietary restriction (DR) decreases body weight, improves health, and extends lifespan. DR can be achieved by controlling how much and/or when food is provided, as well as by adjusting nutritional composition. Because these factors are often combined during DR, it is unclear which are necessary for beneficial effects. Several drugs have been utilized that target nutrient-sensing gene pathways, many of which change expression throughout the day, suggesting that the timing of drug administration is critical. Here, we discuss how dietary and pharmacological interventions promote a healthy lifespan by influencing energy intake and circadian rhythms.

Fig. 1. Crosstalk between molecular components of circadian clock, nutrient-sensing, and metabolic pathways.

Core clock proteins CLOCK/BMAL1 (transcriptional activators) and PER/CRY (repressors) are engaged in an autoregulatory transcriptional/translational feedback loop leading to 24 h oscillations in gene expression, activity and protein levels. The molecular clock also regulates the rhythmic expression of genes involved in several cellular functions and nutrient-sensing pathways, which in turn feedback to the core clock machinery. CLOCK (Clock), BMAL1 (Arntl), PER (Period), CRY (Cryptochrome), SIRT1 (Sirtuin 1), AMPK (5’ AMP-activated protein kinase), PGC-1α (PPARγ co-activator 1a), mTOR (Mammalian target of rapamycin), ROR (RAR- Related Orphan Receptor), Rev-Erb (Nr1d1), and PPAR (Peroxisome Proliferator Activated Receptor).

Fig. 2. Aging-related pathways regulated by dietary interventions display circadian oscillations.

a Dietary interventions influence nutrient-sensing pathways by inducing antiaging (yellow-green gradient) and reducing proaging (pink-purple gradient) molecules. There are known direct interactions between nutrient-sensing pathways involve in aging (SIRT1, AMPK, NAMPT, mTOR) and core clock genes (CLOCK/BMAL and PER/CRY). Several compounds known as caloric restriction mimetics (CRM, shown as gray font color) target specific nutrient-sensing genes and mimic the health benefits of CR without reducing food intake. CRMs tested by ITP and other laboratories include acarbose, curcumin, spermidine, rapamycin, metformin, resveratrol, NAD+ boosters and amino acids (reviewed by ref. ). CRMs (gray font color) are indicated next to or below their molecular targets. b Aging-related genes are expressed in a circadian manner (purple circles) in at least one tissue. Genes that are noncircadian in each tissue are represented as gray circles. RNA-seq and microarray containing circadian datasets for liver and other tissues extracted from CircaDB (http://circadb.hogeneschlab.org, Hogenesch laboratory). Proaging molecules: GH (growth hormone), GHR (growth hormone receptor), IGF-1 (insulin-like growth factor 1), PI3K (Phosphoinositide 3-kinase), AKT (also known as Protein kinase B), and mTOR (Mechanistic or Mammalian target of rapamycin). Antiaging molecules: SIRT1 (Sirtuin 1), AMPK (5’ AMP-activated protein kinase), PGC-1α (PPARγ co-activator 1a), PTEN (Phosphatase and tensin homolog), FOXO (Forkhead Box O). Core clock components CLOCK/BMAL1 (transcriptional activators) and PER/CRY (transcriptional repressors). See also Supplementary Table 1 for additional tissues and aging-related genes in mouse, baboon, and humans.

Fig. 3. Dietary interventions protect against chronic diseases and promote lifespan.

a Dietary restriction improves healthspan in several species by reducing the risk for obesity, diabetes, cardiovascular disease (CVD), hypertension, neurodegeneration, and inflammation. Although these benefits have been associated with a reduction in the number of calories consumed, extending fasting periods, and restricting the timing of food intake, the individual contribution of these factors remains unknown, since classical dietary restriction protocols often combines one or more of these parameters. b Dietary restriction extends lifespan in most model organisms used in aging research. Green circles labeled as “YES” represent dietary interventions that increase both maximum and median lifespan. Green circles with white centers labeled as “YES” represent the extension of median but not maximum lifespan. Red circles labeled as “NO” refer interventions that have no effect on median or maximum lifespan. Gray circles labeled as “?” indicate conditions that have not yet been tested. Although time-restricted feeding (TR) does not extend lifespan in flies, caloric restriction (CR) protocols that promote longevity in monkeys, rats and mice also involve TR as well (shown as green outer circles with gray centers labeled with “?”). Dietary interventions: Caloric Restriction (CR)^,,,. Intermittent Fasting (IF)^, includes either periodic fasting (PF, also known as every-other-day feeding EOD) or 5 days fasting/low calories followed by 2 days unrestricted intake (Weekdays 5:2). Fasting Mimicking Diet (FMD) with 5 days of a low-caloric diet every 3–4 months. Time-restricted feeding (TR), in which food is available ~8–12 h exclusively during the active period.

Fig. 4. Model of how Circadian Medicine can be used as an optimized intervention to improve circadian rhythms and potentially promote lifespan.

The top panel reflects the current evidence that, (1) aging-related pathways oscillate throughout the day; (2) circadian rhythms decline with age and restoring rhythms improves healthspan; and (3) CR, the most robust lifespan-extending intervention, remarkably protects against the age-dependent dampening of circadian rhythms. Circadian medicine introduces a time-of-day concept for administration of drugs. Considering most aging-related genes are circadian, perhaps there is an optimal time for interventions such as CR mimetics (CRMs). The hypothesis behind this model is that there is an optimal time to administer antiaging drugs, which can restore the proper rhythms targets, and consequently boost survival. If there were an optimal time, we would expect robust circadian rhythms even in an aged individual resembling a young state, potentially leading to lifespan extension. On the contrary, a suboptimal time of administration would not be effective or would require a higher dose to reach similar beneficial effect. Tailoring the treatment for each drug as to how often and what time of the day is still required, as it depends on pharmacokinetic properties, tissue-specific pathways, potential sex-differences, and other factors.