SIRT1 Mediates Central Circadian Control in the SCN by a Mechanism that Decays with Aging
Open accessAbstract
SIRT1 is a NAD(+)-dependent protein deacetylase that governs many physiological pathways, including circadian rhythm in peripheral tissues. Here, we show that SIRT1 in the brain governs central circadian control by activating the transcription of the two major circadian regulators, BMAL1 and CLOCK. This activation comprises an amplifying circadian loop involving SIRT1, PGC-1α, and Nampt. In aged wild-type mice, SIRT1 levels in the suprachiasmatic nucleus are decreased, as are those of BMAL1 and PER2, giving rise to a longer intrinsic period, a more disrupted activity pattern, and an inability to adapt to changes in the light entrainment schedule. Young mice lacking brain SIRT1 phenocopy these aging-dependent circadian changes, whereas mice that overexpress SIRT1 in the brain are protected from the effects of aging. Our findings indicate that SIRT1 activates the central pacemaker to maintain robust circadian control in young animals, and a decay in this activity may play an important role in aging.
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In humans and rodent models, the amplitude of peripheral oscillatory rhythms dampens with age.
“In humans and rodent models, the amplitude of peripheral oscillatory rhythms dampens with age”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [241]
These SCN network changes result in desynchronization and a reduction in the amplitude of neuronal activity rhythms and, ultimately, physiological and behavioural rhythms.
“These SCN network changes result in desynchronization and a reduction in the amplitude of neuronal activity rhythms248,249 and, ultimately, physiological and behavioural rhythms241.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [241]
Brain-specific knockout of Sirt1 in rodents is sufficient to phenocopy the effects of ageing on the SCN and circadian behaviour, whereas overexpression of Sirt1 is protective.
“brain-specific knockout of Sirt1 in rodents is sufficient to phenocopy the effects of ageing on the SCN and circadian behaviour, whereas overexpression of Sirt1 is protective241”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [241]
In mice, SCN levels of SIRT1 decline with age, potentially explaining the increase in circadian rhythm disruptions in older people.
“In mice, SCN levels of sirtuin 1 (SIRT1), a metabolic sensing protein and mediator of CLOCK and BMAL1 function (FIG. 1), decline with age, potentially explaining the increase in circadian rhythm disruptions in older people241.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [241]
In mice, reductions of sirtuin activity in the SCN lead to a gradual age-dependent dampening of SCN activity and locomotor rhythms.
“This mouse study reveals that reductions of sirtuin activity in the SCN leads to a gradual age-dependent dampening of SCN activity and locomotor rhythms.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [241]
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- Authors
- Chang, H.-C., & Guarente, L.
- Affiliations
- Massachusetts Institute of Technology (US)
- Corresponding author
- Guarente, Leonard
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 153
- Issue
- 7
- Pages
- 1448-1460
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3748806
- OpenAlex
- W1987699071
- Cited by
- 615
- References
- 56
- Citations by year
- 2026: 21 · 2025: 44 · 2024: 41 · 2023: 39 · 2022: 41 · 2021: 48 · 2020: 59 · 2019: 54 · 2018: 51 · 2017: 63 · 2016: 44 · 2015: 51 · 2014: 44 · 2013: 14
- FWCI
- 27.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Ellison Medical Foundation
- Glenn Foundation for Medical Research
- Life Sciences Research Foundation
- National Institutes of Health
- National Institute on Aging (R56AG015339, R01AG015339, R01AG011119)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- SIRT1, circadian rhythm, suprachiasmatic nucleus, aging, Bmal1, clocks, PGC-1α, visfatin, NAD+ metabolism, protein deacetylation, circadian period, light entrainment, SIRT1 knockout mice, SIRT1 overexpression
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Aging, Animals, Brain, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Promoter Regions, Genetic, Suprachiasmatic Nucleus, Transcription Factors, Trans-Activators, Mice, Sirtuin 1, ARNTL Transcription Factors, Circadian Clocks
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