Molecular Biology of Aging
Research on aging is one of the main scientific challenges of the twenty-first century. The major reason for this is the continual increase in the average human lifespan. Our research aims to elucidate the mechanism of the molecular regulation of aging, and investigate two major pathways that have been shown to regulate lifespan - caloric restriction (CR) and Sirtuin deacetylases. CR has been shown to slow the rate of aging and extend the maximum lifespan of any organism in which it has been tested. In rodents, a reduction of ~30% of the calorie intake imposes an increase of more than 30% in their lifespan. In addition, CR delays many age-related diseases such as cancer, diabetes, neurodegenerative and decline in the function of the immune system. Although CR has been known for more than 70 years to extend lifespan, the molecular mechanism by which it retards aging and how it is regulated are still a speculation.
Studies in model organisms showed that the activity of the Sir2 family of
NAD+-dependent protein deacetylases (sirtuins) is important in regulating lifespan in yeast, worms, and flies. Overexpression of Sir2 in these organisms can extend their lifespan by ~40%, and in some yeast and fly strains, Sir2 mediates the effect of CR on lifespan. Moreover, we recently showed that in mammals, SIRT1, the closest human Sir2 homologue, is induced in multiple tissues upon CR and mediates the protection of CR from cell death.
Our current research focuses on the following topics:
1. The molecular pathways that regulate the response for caloric restriction.
2. The molecular and cellular biology of sirtuin deacetylases.
3. Isolating new proteins that regulate longevity in mammals.
Cohen H. and Sinclair DA. (2001). Recombination-mediated lengthening of terminal telomeric repeats requires the Sgs1 DNA helicase. Proc Natl Acad Sci U S A 98(6):3174-9 (track II).
Cohen H. (2001). Cancer and Aging: Two Sides of the RecQ-Like Helicase Coin?. Geriatrics and Aging 4(2):28-9. (Invited review)
Anderson R., Bitterman K., Wood J., Cohen H., Medvedik O., Lin. SS., Gordon JI. and Sinclair DA. (2002). NPT1 is a limiting component of stress resistance and replicative life span in S. cerevisiae. J Biol Chem 24;277(21):18881-90.
Bitterman KJ., Anderson RM., Cohen HY., Latorre-Esteves M. and Sinclair DA.
(2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem 277(47):45099-107.
Howitz KT., Bitterman KJ., Cohen HY., Lamming DW., Lavu S., Wood JG., Zipkin RE., Chung P., Kisielewski A., Zhang LL., Scherer B. and Sinclair DA. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425(6954):191-6.
Cohen HY., Lavu S., Bitterman KJ., Hekking B., Imahiyerobo TA., Miller C., Frye R., Ploegh H., Kessler B., and Sinclair DA. (2004). Acetylation of the C-terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Molecular Cell 13(5): 627-38.
Brunet A., Sweeney LB., Sturgill F., LinY., Tran H., Cohen HY., Hu LS., Gigy SP., Sinclair DA. Alt FW. and Greenberg ME. (2004). The sir2 longevity gene regulates FOXO transcription factor function through deacetylation. Science 303: 2012-5.
Cohen HY., Miller C., Bitterman KJ., Hekking B., Kessler B., de Cabo R., Gorospe M. and Sinclair DA. (2004) Calorie restriction promotes cell survival by inducing SIRT1. Science 305: 390-2.
Cohen HY., Bitterman KJ. and Sinclair DA. (2003). Metabolic regulation of gene silencing and life span. In Aging at the Molecular Level 193-211. Kluwer Academic Publishers, B.V., The Netherlands.