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Aging: Rewiring the circadian clock

September 2017
Nature Structural & Molecular Biology 24(9):687-688

Authors:

University of California, Berkeley

The robustness of the circadian clock deteriorates with aging. Two new studies show that aging reprograms the circadian transcriptome in a cell-type-dependent manner and that such rewiring can be reversed by caloric restriction.

Aging reprograms the circadian transcriptome in a cell-type-dependent manner. Aged epidermal and skeletal muscle stem cells lose oscillating transcription of genes that regulate homeostasis but gain oscillating expression of genes mediating stress responses. Oscillatory genes involved in NAD + metabolism and protein acetylation are enriched in the liver. Such rewiring can be reversed in part by the administration of the CR diet.

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nature structural & molecular biology volume 24 number 9 september 2017 687

all three cell types, illustrating a remarkable tis-

sue- or cell-type specificity in aging-associated

reprogramming of the clock. Aged epidermal

and skeletal muscle stem cells lost oscillation

of homeostasis genes but gained oscillation

in genes mediating a stress response to DNA

damage and inflammation or autophagy6. In

contrast, oscillatory genes involved in NAD+

metabolism and protein acetylation figured

prominently in the liver5 (Fig. 1).

Surprisingly, the expression of core clock

genes and clock-controlled genes remained

unchanged with aging, despite the drastic

circadian reprogramming5,6. Thus, the core

clock machinery remains largely intact in old

age, giving hope for the prospect of reversing

aging-associated circadian reprogramming to

potentially improve physiological functions.

Indeed, CR-induced robust reprogramming

of the circadian transcriptome partially over-

laps with the circadian transcriptome in young

mice5,6. Thus, the profound physiological

impact of CR may be, in part, mediated by the

reprogramming of the circadian clock.

The subject of calorie restriction (CR) is of

wide interest because it is the most robust

intervention to extend mammalian lifespan.

More impressively, it reverses aging-associated

physiological decline and ameliorates a wide

spectrum of diseases1,2. It was thought that

this dietary regimen elicits its health ben-

efits through a passive effect of reduced meta-

bolic rate. However, recent advances in aging

research favor the view that the organismal

effects of mammalian CR are actively regulated

processes3,4. Two recent studies by Sato et al.5

and Solanas et al.6 reveal that aging reprograms

the circadian transcriptome in a cell-type-de-

pendent manner and that such rewiring can be

reversed by the administration of the CR diet.

These findings provide high-resolution molec-

ular ‘fingerprints’ of the circadian response to

physiological aging and CR and add new evi-

dence for the emerging concept that aging-

associated conditions can be reversed7–9.

A large number of physiological events

follow circadian rhythms. It has been specu-

lated that the robustness of circadian rhythms

deteriorates with age, accounting for much of

aging-associated physiological decline10–12.

Taking a systems biology approach, Sato et al.

and Solanas et al. profiled the circadian tran-

scriptome of the liver, epidermal and skeletal

muscle stem cells of young and aged mice fed

either ad libitum or a CR diet5,6. Strikingly,

a large number of oscillatory transcripts

(1,400–2,600) in young mice lost their rhyth-

mic expression in old mice, whereas numerous

de novo oscillating genes (~1,600 in all three cell

types) were observed exclusively in old mice.

These findings provide compelling molecular

evidence that aging is associated with a signifi-

cant reprogramming of the circadian clock and

that this phenomenon is conserved across tis-

sues and cell types.

An interesting finding came from direct com-

parison of the age-specific oscillatory transcripts

from the three cell types. Very few oscillatory

transcripts were consistently altered with age in

Aging: rewiring the circadian clock

Rika Ohkubo & Danica Chen

The robustness of the circadian clock deteriorates with aging. Two new studies show that aging reprograms

the circadian transcriptome in a cell-type-dependent manner and that such rewiring can be reversed

by caloric restriction.

Rika Ohkubo and Danica Chen are at the

Program in Metabolic Biology, Nutritional

Sciences & Toxicology , University of California,

Berkeley, Berkeley, California, USA.

e-mail: danicac@berkeley.edu

How does rewiring of the circadian clock

contribute to cellular aging? A closer look at

the phases of the circadian genes and their

regulated cellular processes in young and old

mice might offer a clue. In young epidermal

stem cells, DNA replication takes place at night,

whereas maximal oxidative phosphorylation

occurs during the day13,14. It was thought that

temporal segregation of DNA replication and

oxidative phosphorylation at different times

of the 24-h cycle ensures that unwound DNA

is exposed to minimal oxidative stress and

thereby prevents DNA damage. Solanas et al.

now found that in aged epidermal stem cells,

DNA replication was delayed and extended

into the daytime, whereas the phase of oxidative

phosphorylation remained unchanged6. Thus,

rewiring of the circadian clock with age can lead

to misalignment of cellular activities and the

resulting accumulation of cellular damage.

Taken together, these new findings also

open up many questions. If the core clock

machinery remains intact during aging, what

are the driving forces of aging-associated

Figure 1 Aging reprograms the circadian transcriptome in a cell-type-dependent manner. Aged

epidermal and skeletal muscle stem cells lose oscillating transcription of genes that regulate

homeostasis but gain oscillating expression of genes mediating stress responses. Oscillatory genes

involved in NAD+ metabolism and protein acetylation are enriched in the liver. Such rewiring can be

reversed in part by the administration of the CR diet.

Calorie restriction

Aging

Acetylation and

NAD+ metabolism

Homeostasis

Stress

response

Muscle and skin

stem cells

Liver

111

210

Kimberly Caesar/Springer Nature

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688 volume 24 number 9 september 2017 nature structural & molecular biology

circadian reprogramming, and what are the

mediators of CR-induced circadian reprogram-

ming? The observed enrichment of circadian

genes related to NAD+ metabolism, protein

acetylation, and stress resistance points to the

sirtuin family of NAD+-dependent deacety-

lases as potential mediators of reprogramming.

Sirtuins are known to extend mammalian

lifespan and healthspan15,16, mediate aspects of

the CR response3,4, and have increasingly been

appreciated as stress-resistance regulators4,7,9,17.

Fittingly, several sirtuins have been implicated in

circadian control18 and there is some degree of

overlap between SIRT1-dependent hepatic circa-

dian genes and aging- or CR-associated hepatic

circadian genes5. Further studies are needed to

determine whether overexpression of SIRT1 or

other mammalian sirtuins (SIRT2–SIRT7) pre-

vents aging-associated circadian reprogramming

and whether CR induces circadian reprogram-

ming in the absence of sirtuins.

It is now widely accepted that the general

cause of aging is the accumulation of cellular

damage19,20. Aging-associated stress resis-

tance is particularly relevant to adult stem

1. Luo, H., Chiang, H.H., Louw, M., Susanto, A. & Chen,

D. Trends Endocrinol. Metab. 28, 449–460 (2017).

2. Weindruch, R. & Walford, R.L. The Retardation of Aging

and Disease by Dietary Restriction (Charles C. Thomas

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Cell Metab. 12, 662–667 (2010).

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6. Solanas, G. et al. Cell 170, 678–692 (2017).

7. Brown, K. et al. Cell Rep. 3, 319–327 (2013).

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9. Mohrin, M. et al. Science 347, 1374–1377 (2015).

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11758–11763 (2012).

14. Stringari, C. et al. Cell Rep. 10, 1–7 (2015).

15. Finkel, T., Deng, C.X. & Mostoslavsky, R. Nature 460,

587–591 (2009).

16. Kanfi, Y. et al. Nature 483, 218–221 (2012).

17. Shin, J. et al. Cell Rep. 5, 654–665 (2013).

18. Masri, S. & Sassone-Corsi, P. Sci. Signal. 7, re6 (2014).

19. López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M.

& Kroemer, G. Cell 153, 1194–1217 (2013).

20. Vijg, J. & Campisi, J. Nature 454, 1065–1071

(2008).

cells, which persist throughout the organis-

mal lifespan to repair and maintain tissues7,9.

The aging-associated circadian reprogram-

ming of both homeostasis and stress-

resistance genes observed in adult stem cells

suggests that increased cellular damage is a

driver of aging-associated circadian repro-

gramming. Given that aging-associated

accumulation of DNA damage in stem cells

originates from exposure to mitochondrial

stress6 and that the mitochondrial protective

programs are repressed in aged adult stem

cells7,9, it is tempting to speculate that reac-

tivating the mitochondrial protective pro-

grams may provide a means to reduce the

accumulation of cellular damage and reverse

aging-associated circadian reprogramming.

ACKNOWLEDGMENTS

D.C. is supported by NIH grant R01DK101885,

the National Institute of Food and Agriculture, the

PackerWentz Endowment and the Chau Hoi Shuen

Foundation. R.O. is supported by the ITO Scholarship

and the Honjo International Scholarship.

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

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In neurons, SNARE proteins mediate the fusion of neurotransmitter-

containing vesicles with the plasma membrane, leading to the release of

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previously known, or primary, interface. The second C2B domain (orange) interacts with the SNARE complex and with Cpx (light blue),

in what the authors call a ‘tripartite interface’. This interface (marked by a dashed box in the figure) involves the conserved HA a-helix in

C2B, which extends the Cpx a-helix that interacts with the SNARE complex.

Mutagenesis analyses of the tripartite interface show that it is required for Ca2+-triggered synchronous release by neurons, as is the

primary interface. Thus, both binding interfaces are essential to reach the primed prefusion state captured in the new structure.

However, the tripartite interface also serves to ‘lock’ the complex in a primed state; thus, Syt1 and Cpx cooperate to prevent calcium-

independent vesicle fusion. The tripartite interface would be unlocked upon Ca2+ binding to the C2 domains, which would likely result

in release of the Syt1 C2B domain involved in the tripartite complex and conformational rearrangements of the remaining complex.

This proposed unlocking mechanism remains to be confirmed, but the present findings can already explain the phenotypes of Cpx or

Syt1 knockouts and of dominant-negative Syt1 mutations.

Inês Chen

HAHA

195

244

Synaptobrevin-2

SNAP-25_C

Syntaxin-1A

SNAP-25_N

Syt1 C2A

Ca2+–binding site

Ca2+–binding

site

Syt1 C2B

Cpx

Ca2+–binding

site

990 Å2

720 Å2

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