Are sirtuins a mammalian fountain of youth? The question has been raised and dismissed many times, and now a new study suggests that yes, perhaps they are, when they bubble up in the right place. In the September 3 Cell Metabolism, scientists led by Shin-ichiro Imai, Washington University School of Medicine, St. Louis, argue that Sirt1 makes mice live longer and age better, but only when expressed in specific neurons of the hypothalamus. The sirtuin seems to work in part by keeping skeletal muscle young. "We clearly demonstrate that Sirt1 extends lifespan," Imai told Alzforum. "It seems to influence some core mechanism of aging."

Sirtuins play a role in metabolic regulation (see Haigis and Sinclair, 2010), but controversy has surfaced over whether the proteins influence aging and longevity. Sir2 was previously shown to lengthen lifespan in worms (see Tissenbaum and Guarente, 2001), but scientists later challenged that result (see ARF related news story on Burnett et al., 2011). Several studies suggested that sirtuins mediate the lifespan-lengthening effects of caloric restriction (for example, see Someya et al, 2010), but a 2011 study suggested that whole-body Sirt1 expression did not prolong life, at least in mammals (see Herranz et al., 2010). Recently, Imai's group reported that Sirt1 expression specifically in the hypothalamus mediates the physiological benefits of dietary restriction (DR), and that a restricted diet boosts Sirt1 and neuronal activation in certain hypothalamic nuclei in mice (see Satoh et al., 2010). The hypothalamus is the main control center for the autonomic nervous system. It regulates sleep, body temperature, appetite, and metabolic activities. The scientists wanted to know if mimicking this hypothalamus-specific Sirt1 upregulation in mice eating regular chow would recreate the lifespan lengthening observed in DR mice.

To investigate, first author Akiko Satoh and colleagues used mice they previously engineered to overexpress Sirt1 only in the brain. Called BRASTO, these animals are similar to wild-type mice that undergo dietary restriction in that they make more Sirt1, particularly in the dorsomedial and lateral hypothalamic nuclei. On an normal diet regimen, BRASTO mice lived 11 percent longer than their wild-type counterparts. Compared to age-matched controls, 20-month-old BRASTO mice maintained higher body temperatures, were more physically active, spent more energy, and consumed more oxygen during their active hours at night—just as younger mice do. They also slept more deeply during the day, as measured in non-rapid eye movement sleep. These results suggest that physiological aging slows down in BRASTO mice compared to controls.

The benefit appears to hinge at least in part on skeletal muscle. In aged wild-type mice, individual segments of muscle fibers called sarcomeres appeared disordered under the electron microscope, and the adjacent mitochondria enlarged, fused, or absent. In contrast, aged muscle in BRASTO mice possessed orderly sarcomeres and more normal mitochondria.

Curiously, another BRASTO mouse line that overexpressed Sirt1 throughout the brain and more uniformly throughout all nuclei in the hypothalamus exhibited none of these signs of youth. That suggests that Sirt1 specifically in the dorsomedial and lateral hypothalamus is important for the anti-aging effect. Imai speculates that this could help settle the controversy about the role of Sirt1 aging in mice as high Sirt1 expression throughout the body might suppress neural activity in the dorsomedial and lateral hypothalamus. Future research is needed to explore that possibility, he told Alzforum.

This adds to a number of recent papers suggesting that sirtuins mediate longevity, said Leonard Guarente, Massachusetts Institute of Technology, who is an early proponent of the idea. "I think that discussion is being settled," he said, adding that this study highlights the importance of the brain as a central controller in regulating the body's aging process. He pointed out that while drugs can modify sirtuins, the proteins' effects are wide-ranging, hence drug intervention could affect many systems at once. If scientists can figure out how to concentrate Sirt1-enhancing drugs in the right places, they might be able to treat aging and even age-related diseases such as Alzheimer's, he said (see ARF related news story on Donmez et al., 2010). Guarente co-chairs the scientific advisory board for the pharmaceutical company GlaxoSmithKline, which is pursuing sirtuin-based drugs.

Currently, available compounds such as resveratrol activate Sirt1 on a systemic level (see ARF related news story) but do not enter the brain well. Imai said that his lab members are working to control Sirt1 action specifically in the hypothalamus. They are examining how application of nicotinamide mononucleotide, an intermediate of the nicotinamide dinucleotide enzyme cofactor required for Sirt1 activity, could raise Sirt1 activation in the brain. They also want to pin down why Sirt1 directs its signal specifically to skeletal muscle, and whether the skeletal muscle in turn secretes something to affect aging in the whole body.—Gwyneth Dickey Zakaib

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Comments on News and Primary Papers

  1. The role of SIR2 orthologs in modulating longevity is currently a subject of major debate. While overexpression ofSIR2 extends lifespan in yeast, studies in worms and flies remain inconsistent and whole body over expression of the mouse ortholog, SIRT1, failed to extend lifespan, although protection against some age-related diseases has been observed. This study from the Imai lab is important because it shows that overexpression of SIRT1 can extend mammalian lifespan. It is also interesting because increasing evidence implicates the role of the hypothalamus in regulating processes linked to aging. Imai’s work shows that the aging specific function of SIRT1 may relate to improved hypothalamic control of tissue communication and metabolism.

    View all comments by Brian Kennedy

References

News Citations

  1. Sirtuins’ Status Less Certain as Study Questions Longevity Effect
  2. Research Brief: SIRTs Keep Brain Minty Fresh
  3. SIRT1, Resveratrol and More: Moving Closer to Anti-aging Elixir?

Paper Citations

  1. . Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253-95. PubMed.
  2. . Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 2001 Mar 8;410(6825):227-30. PubMed.
  3. . Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature. 2011 Sep 22;477(7365):482-5. PubMed.
  4. . Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell. 2010 Nov 24;143(5):802-12. PubMed.
  5. . Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun. 2010;1:3. PubMed.
  6. . SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. J Neurosci. 2010 Jul 28;30(30):10220-32. PubMed.
  7. . SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell. 2010 Jul 23;142(2):320-32. PubMed.

Further Reading

Papers

  1. . Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature. 2011 Sep 22;477(7365):482-5. PubMed.
  2. . Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253-95. PubMed.
  3. . Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 2001 Mar 8;410(6825):227-30. PubMed.
  4. . Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun. 2010;1:3. PubMed.
  5. . SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell. 2010 Jul 23;142(2):320-32. PubMed.
  6. . SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. J Neurosci. 2010 Jul 28;30(30):10220-32. PubMed.

Primary Papers

  1. . Sirt1 Extends Life Span and Delays Aging in Mice through the Regulation of Nk2 Homeobox 1 in the DMH and LH. Cell Metab. 2013 Sep 3;18(3):416-30. PubMed.