Aging in mice
The mammalian sir2 ortholog Sirt1 has several functions that trigger physiological changes seen during CR. First, Sirt1 makes cells more resistant to oxidative or radiation-induced stress, which is a phenotype of rodent cells from CR animals. Second, Sirt1 promotes mobilization of fat from white adipose tissues, a change triggered by CR that is sufficient to extend the life span. It does this by modulating the activity of the key regulator of white fat, PPARg. Third, Sirt1 mediates the metabolism of energy sources in metabolically active tissues. CR animals are efficient in metabolism rendering them insulin-sensitive. Fourth, Sirt1 regulates the induction of insulin in pancreatic beta cells, an obvious component of energy utilization during CR. In several cases, Sirt1 is activated by starvation or stress to carry out these functions. Molecular mechanisms of Sirt1 activation and its functions in triggering the physiological changes elicited by CR are under study.
There are six other mammalian SIR2-related genes (or sirtuins) besides Sirt1. Functional studies of Sirt2, 3, 4, and 7 are being carried out. At least some of them also appear to play a role in CR. Sirt2 appears to regulate insulin sensitivity in mice. Recent findings also show a possible link between Sirt2 and cancer. Sirt4, like Sirt1, plays a role in regulating insulin production in beta cells. This regulation is mediated from the mitochondria, the cellular compartment where Sirt4 resides. Knock out mice for Sirt1-4 are available for these studies.
Aging in C. elegans
C. elegans has four SIR2 homologs. Strains with a free duplication of the SIR2 ortholog, sir-2.1, show a significantly extended life span. Transgenic animals with elevated levels of sir-2.1 also live longer than wild type. A deletion of sir-2.1 has the opposite effect, life span is shortened. sir-2.1 appears to function in the insulin signaling pathway shown to regulate aging and dauer formation in C. elegans. This gene may also function in a second pathway to regulate life span. In another project, the possible role of cell death genes in limiting organismal life span is under study.
Sirtuins in early-life nutrition
Sirtuins have been implicated in nutrition-related longevity through a variety of mechanisms. It was recently demonstrated that SIRT1 expression is altered in progeny in response to maternal high-fat diets in non-human primates. Because of the ability of SIRT1 to epigenetically alter gene expression in response to one’s nutritional state, we are interested in exploring whether embryonic SIRT1 mediates health and longevity in mammalian offspring exposed to different prenatal nutritional regimens.
Circadian clock regulation
Along with modulating nutritive aspects of mammalian physiology, SIRT1 has been implicated in the function of circadian rhythms. Circadian clock-controlled rhythms are responsible for maintaining temporal programming that is essential for behavioral and physiological coordination. We have recently demonstrated that SIRT1 in the brain directs the central circadian clock by regulating transcription of BMAL1 and CLOCK, two crucial components modulating circadian rhythms. Importantly, the normal decay in the function of the central circadian clock with aging can be suppressed by over-expression of SIRT1 in the brain. This signifies an important role for SIRT1 in chronomodulation that may have implications for aging and other age-related disorders, including cancer and metabolic syndrome.
Sirtuins and neurodegeneration
There is mounting evidence that increasing the levels or activity of sirtuins may slow the rate of brain aging and be protective in neurodegenerative disease. Sirt1 overexpression decelerates age-related transcriptional changes in mouse frontal cortex, suggesting that Sirt1 may slow mouse molecular brain aging. Furthermore, it has been shown by us and others that Sirt1 overexpression is able to slow progression, decrease neuropathology, and increase lifespan in Alzheimer’s, Huntington’s, and Parkinson’s disease mouse models. Sirt2 inhibitors are able to rescue pathology in cell culture and drosophila Parkinson’s and Huntington’s disease models, and also in a mouse model of frontotemporal dementia. The role and mechanism for the other Sirtuins in brain aging and neurodegeneration remains to be explored.
Aging of the human brain
Age is the biggest risk factor and a requirement for onset of many neurodegenerative diseases for reasons that remain unclear. Human brain aging is associated with specific and robust changes in the expression of 5-10% of the genome. These changes are highly reproducible and precise and tend to effect neurodegenerative disease genes disproportionally, suggesting that brain aging may be a “transcriptional program” that is permissive for neurodegenerative disease onset. It is one of our goals to understand how the human brain aging transcriptional program works and how it is regulated to pave the way for anti-aging therapeutic strategies for neurodegenerative disease. We are employing human post-mortem transcriptomic, whole genome SNP chips, epigenomic, and bioinformatic strategies to understand this problem. We have ongoing collaborations with other labs and clinicians at MIT, Harvard, and the Broad Institute, including the lab of Dr. Manolis Kellis (computational biology and epigenetics). We are particularly interested in the role of sirtuins in human brain aging and neurodegeneration. We are investigating the role of sirtuin levels and also sirtuin polymorphisms in regulating human brain aging rates and neurodegenerative disease risk as well as looking broadly using unbiased genome-wide strategies.
Kubova, J., and Guarente, L. How does calorie restrriction work? Genes and Dev. 17, 313- 321, (2003).
Hekimi, S. and Guarente, L. Genetics and the specificity of the aging process. Science, 299, 1351-1354, (2003).
Lin, S. J., Ford, E., Haigis, M., Liszt, G., and Guarente, L. Calorie restriction extends life span by lowering the level of NADH. Genes Dev. 18, 12-16, (2004).
Motta, M. C., Divecha, N., Lemieux, M., Kamel, C., Chen, D., Gu, W., Bultsma, Y., McBurney, M., and Guarente, L. Mammalian SIRT1 represses forkhead transcription factors. Cell 116, 551-563, (2004).
Picard, F., Kurtev, M., Chung, N., Topark-Ngarmm, A., Senawong, T, Machado de Oliveira, R., Leid, M, McBurney, M. and Guarente, L. SIRT1 regulates white fat in mice:a mechanistic link between calorie restriction and aging. Nature, 429, 771-776. published online June 2, (2004).Donmez, G., Wang, D., Cohen, D., and Guarente, L. (2010). SIRT1 suppresses beta-amyloid production by activating the alpha-secretase ADAM10. Cell 142, 320-332.
Guarente, L. (2011). Sirtuins, Aging, and Medicine. New England Journal of Medicine, 364, 2235-2244.
Hyunkyung, J., Cohen, D, Cui, L., Supinski, A., Savas3, J., Mazzulli, J., Yates, J., Bordone, L., Guarente, L., and Krainc, D. (2011). Sirt1 mediates neuroprotection from mutant huntingtin by activation of TORC1and CREB transcriptional pathway. Nature Medicine, online Dec. 18.
Libert, S., Pointer, K., Bell, E., Das, A., Asara, J., Kapur, K, Bergmann, S., Preisig M., Otowa, T., Kendler, K., Chen, X., Hettema, J., van den Oord, E., Rubio, J., and Guarente, L. (2011). SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive. Cell 147, 1459-1472.
Simic, P., Zainabadi, K., Bell, E., Sykes, D., , Saez, B., Lotinun, B.,, Baron, R.,, Scadden, D., Schipani, E.,, and Guarente, L. SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating β-catenin. (2013). EMBO Mol. Med. 3, 430-440 Epub Jan 30.
Simic, P., Williams, EO, Bell, E., Gong, JJ, Bonkowski, M., and Guarente, L. (2013). SIRT1 suppresses the epithelial to mesenchymal transition in cancer metastasis and organ fibrosis. Cell Reports April 10 Epub.
Chang, H-C., and Guarente, L., (2013). SIRT1 mediates central circadian control in
the SCN by a mechanism that decays with aging. Cell 153, 1448-1460.