We are currently working on several different projects related to longevity, aging-associated diseases, metabolism and SIRT6.
Some projects from our lab include:
Role of SIRT6 in aging:
Significant amount of research elucidated the role of the NAD+ dependent SIRT6 deacylase as a key regulator of healthy aging. Previously, we showed that mice overexpressing SIRT6 (MOSES mice) have increased lifespan. Moreover, strikingly, old MOSES mice are less susceptible to a spectrum of aging-related dysfunctions. In addition, SIRT6 has a fundamental protective role against age related diseases. These include for example; its role as tumor suppressor negatively regulates tumor metabolism by inhibiting the Warburg effect, its function in prevention neurodegenerative diseases and in restoring the normal physical activity in old age. Thus, our expanding understanding on SIRT6 regulated mechanisms can enable us to translate this knowledge into human therapy.
Molecular mechanism of Frailty:
Frailty is a geriatric syndrome characterized by weakness, weight loss and low activity. Frailty appears to reflect accumulated damage across multiple systems, include: inflammation, loss of stem cell regeneration, DNA damage and changes in metabolism. We found that aged mice over expressing SIRT6 had less Frailty phenotypes compared to wild type. SIRT6 optimizes energy homeostasis in old age mice, partially by maintaining normally glucose level and youthful metabolome. Therefore, SIRT6 delay frailty and preserve healthy aging. We are currently investigating other interesting and important mechanisms by which SIRT6 affect human Frailty.
Role of SIRT6 on healthy liver:
SIRT6 coordinates and regulates various metabolic pathways. SIRT6 plays a critical role in glucose and fat metabolism and its overexpression protect against obesity related pathologies. Thus, it can serve as a therapeutic target for treating fatty liver disease, the most common cause of liver dysfunction in humans. We found that SIRT6 inhibits cholesterol and triglyceride biosynthesis by inhibiting SREBP1/2, and controls hepatic fat metabolism by repressing miR122. In addition, SIRT6 induces fatty acid and a.a catabolism in the liver, mimicking the effect of fasting and CR. Overall, SIRT6 regulates the cellular decision of energy source utilization. Therefore, we are searching of new and relevant SIRT6 activities that will reveal new mechanisms by which SIRT6 maintains healthy liver.
Metabolism of physical exercise:
The aging process is accompanied with a variety of physiological changes of the function of cells and tissues. Studies have shown that exercise reduces the odds of age related developing of heart diseases, stroke, diabetes and improves muscle function. In addition, aerobic exercise is associated with a reduced risk of cognitive impairment and dementia. In our lab we are investigating the molecular mechanisms underlying these effects of physical exercise that are relevant to aging. Furthermore, we believe that this knowledge can help humanity to discover new treatments and drugs for the elderly population that prevent age- related diseases.