Identify novel molecular gerontological targets that affect susceptibility to a variety of age-related diseases through control of lifespan.

Research into sirtuins, and other as yet uncharacterized “longevity” genes, has significant commercial ramifications. Insights generated from the Sinclair lab have contributed signficiantly to the development of small molecule therapeutics that target sirtuins. Their studies demonstrate that activation of particular sirtuin deacetylases is a key event that links calorie restriction to prolonged lifespan. This link lays the foundation for future studies directed toward identifying novel molecular gerontological targets that affect susceptibility to a variety of age-related diseases through control of lifespan. These diseases include cancer, cardiovascular disease, and neurodegenerative disorders. Dr. Sinclair’s laboratory is undertaking a variety of approaches in its investigations of sirtuin biology, striving to find the common “nodes” where longevity genes and disease genes intersect. These studies have enormous potential for molecularly deciphering the link between aging and aging-related diseases. Moreover, these experimental inquiries should yield vital information that will facilitate the design of screening efforts for therapeutics that can extend lifespan, improve the quality of life, and guard against aging-related diseases. 
 

Dr. Sinclair is:

• Studying the molecular signaling pathways that mediate the life extension function of the sirtuin gene family, including both cytoplasmic and mitochondrial-localized family members.
   
• Employing a variety of available mouse disease models, as well as designing novel mouse genetic models, that can be employed for dissecting the links between sirtuin biology and disease processes.
   
• Identifying longevity genes that possess overlapping activities with disease processes, and investigating the regulation of these genes (that is, gene expression, translation, and so on).
   
• Investigating sirtuin biology in the context of mitochondrial and cellular metabolism.
   
• Exploring the relationship of the TOR signaling pathway to sirtuin activity.
   
• Studying the effects of resveratrol, and other related compounds, in modulating sirtuin biology.

• Research the involvement of sirtuins in plant stress resistance

Dr. Sinclair’s laboratory has been investigating the molecular basis of aging and the relationship of aging to some major chronic diseases of the developed world, including cancer and heart disease. By understanding the genes and metabolic pathways that impact cell survival, rational-based interventions can be devised to counteract the aging process, and forestall and reduce the prevalence of age-related diseases.
The lab has extensively studied sirtuins; these proteins are a class of evolutionary conserved proteins that typically display deacetylase activity, and have been found to extend the lifespans of lower organisms. Sirtuins are also responsible for mediating the lifespan prolongation that accompanies calorie restriction. The laboratory’s high-profile studies, which explored the sirtuin-dependent molecular mechanisms culminating in extended lifespans, have been recently published in prestigious journals such as Cell and Nature. The laboratory showed that when cells are exposed to genotoxic stress, the mitochondrial levels of NAD(+), along with the two mitochondria sirtuins Sirt3 and Sirt4, are crucial for cell survival. The laboratory has also investigated the relationship of the TOR (target of rapamycin) signaling axis to calorie restriction and sirtuin activity in yeast. Intriguingly, the lab discovered that when the TOR pathway output diminishes, it leads to enhanced yeast cell survival, which is mediated by Sir2. This finding suggests that the TOR pathway and Sir2 may act through common downstream events, and promote cell survival.

Another facet to the sirtuin story relates to the compound resveratrol. This compound is found naturally in nature and is known to prolong survival of lower organisms by affecting Sir2 activity. Based on a biomarker analysis, Dr. Sinclair’s lab found that Resveratol elicits a clear health benefit to mice that are fed high-calorie meals.
 

Biological Mechanisms and Pathways

• Aging •
• Calorie restriction •
• Deacetylase •
• Inflammation •
• Lifespan •
• Mitochondria •
• NAD(+) •
• Oncology •
• Physiology •
• Sirtuin •
• Target of Rapamycin (TOR)
•  

Cancer

• Cancer •
• Oncology
•  

Disease Mechanisms

• Atherosclerosis •
• Cancer •
• Cardiovascular disease •
• Diabetes •
• Inflammation •
• Neurodegeneration •
• Osteoporosis
•  

Metabolism; Metabolic Disease and Aging

• Aging •
• Energy metabolism •
• NAD(+) •
• Sirtuin
•  

Research Tools and Instrumentation

• C. elegans •
• Mammalian cells •
• Mouse models •
• Yeast
•  

Therapeutic Discovery Tools and Assays

• Atherosclerosis •
• Cancer •
• Cardiac function •
• Cell senescence •
• Mammalian cells •
• Mouse models •
• NeuroD •
• Yeast
•  

Therapeutics

• Resveratol •
• Small molecules
•