May 2020

ENDOCRINOLOGY

COMPOUND INFLUENCES AGE-RELATED DECLINE IN CIRCADIAN RHYTHMS

Featuring: Joseph Bass, MD, PhD

​​Supplementing the diet of lab animals with a chemical supplement that produces a compound called NAD+ reversed certain age-related declines in circadian rhythm function, according to a recent study published in Molecular Cell.

NAD+ supplemented mice avoided declines in circadian clock activity during nighttime, uncovering new interactions between the genetic components of circadian rhythm and aging, according Joseph Bass, MD, PhD, the Charles F. Kettering Professor of Medicine and senior author of the study.

“The elevation of NAD+ has broad effects on gene expression, and effects that differ depending on the time of day you examine tissues,” said Bass, who is also director of the Center for Diabetes and Metabolism and chief of Endocrinology in the Department of Medicine. “As these mice age, their sleep pattern changes, and we observed that the changes could be attenuated with NAD+.”

Nicotinamide adenine dinucleotide (NAD+) is a chemical compound used as a cofactor in a variety of chemical reactions throughout the body. One such function is in DNA repair, which is required in greater amounts as organisms age. In addition, previous studies have shown that NAD+ controls enzymes that regulate genes that in turn control lifespan, according to Bass.

Separately, as more scientists investigated the molecular “clock”,  a series of gene transcription factors that controls circadian rhythm, an unexpected convergence occurred: the same enzymes that regulated lifespan were also found to be connected to the genes that control the clock and its major output — the sleep-wake cycle.
“We had shown the NAD+ and clock processes had links, but we didn’t understand how and we didn’t understand the implications for aging,” Bass said.

In the current study, Bass, along with Daniel Levine, a PhD student in the Driskill Graduate Program in Life Sciences (DGP) and first author of the study, supplemented mouse diets with an NAD+ precursor and uncovered the effects on the molecular regulation of circadian rhythm.

The investigators found that NAD+ supplementation had large effects on gene expression, including a modification on a precise part of the molecular clock sequence that in turn controls the abundance of clock proteins. In older mice, this process has deteriorated, especially in the evening, but additional NAD+ maintained stability of core clock proteins.

NAD+ is also important for immune cell activation and DNA repair, and as organisms age their immune systems become weaker and they become more susceptible to DNA damage — making age-related NAD+ decline a possible explanation, according to Bass.
“A future direction of this work is asking what implications does this have for the immune system and for processes such as cancer,” Bass said. “There are clearly changes in the immune system that have to do with NAD+, but we do not yet know the intersections between aging, immunometabolism and the molecular clock.”

This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK090625, R01DK100814, 1R01DK113011-01A1, 5K01DK105137-03 and 1R03DK116012-01; the Chicago Biomedical Consortium; the National Institute on Aging (NIA) grant; the National Research Service Award F30DK116481; the Swedish Research Council grant 2014-6888; the Swedish Society for Medical Research; the National Institute of Neurological Disorders and Stroke (NINDS) grant R21NS099813; the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL147545; the Roy J. Carver Trust; the NSF-Simons Center for Quantitative Biology grant SFARI 597491-RWC; and the National Science Foundation grant 1764421.

This article was originally published in the Feinberg School of Medicine News Center on May 20, 2020 . 
Joseph Bass, MD, PhD, the Charles F. Kettering Professorship of Medicine, director of the Center for Diabetes and Metabolism and chief of Endocrinology in the Department of Medicine, was senior author of the study published in Molecular Cell.

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