Aging affects all living organisms, which is characterized by the loss of cellular homeostasis causing systemic cellular dysfunction. In fact, both the mitochondrion and the actin cytoskeleton show age-associated declines in functions. As an organism ages, mitochondria accumulate mtDNA mutations, which result in mitochondrial dysfunction. The actin cytoskeleton also declines with age. This affects establishment and maintenance of cell polarity as well as cellular and intracellular movement, which in turn contributes to age- associated declines in systems including the immune system and skeletal muscle. In addition, many age- related pathologies like neurodegenerative diseases, such as Alzheimer's, display dysfunction in mitochondria and actin. Interestingly, Dr. Liza Pon's lab has established actin cytoskeleton dynamics as a contributor to mitochondrial quality control and asymmetric inheritance of mitochondria during cell division. Specifically, in yeast as in other organisms babies are born young, largely independent of the age of the mother. The finding that this process, mother-daughter age asymmetry, occurs in yeast, a single cell organism, led to the model that aging determinants may be preferentially retained by mother cells and rejuvenating determinants are preferentially inherited by daughter cells. Our lab has shown that mitochondria are asymmetrically inherited during yeast cell division and that inheritance of fitter mitochondria by yeast daughter cells is dependent upon that actin cytoskeleton and necessary for daughter cells fitness and lifespan. We carried out a genome-wide screen to identify genes who deletion reduced the sensitivity of yeast to the growth inhibiting effects by an actin destabilizing drug. I obtained evidence for a role of a previously uncharacterized open reading frame identified in this screen in stabilization of actin cables, promoting mitochondrial function, as well as extension of yeast lifespan and healthspan. My preliminary evidence also support a role for this gene as a regulator of the TORC1 pathway, a conserved nutrient sensing pathway that regulates lifespan, through its effect on sensing of branched chain amino acids. Emerging evidence also supports TORC1 in control of actin dynamics. We propose to study 1) how this gene affects the age-associated changes in actin cables and mitochondria; 2) whether the lifespan extension observed upon deletion this gene is a consequence of effects on actin cable stability, retrograde flow and/or mitochondria; 3) whether other interventions that affect actin cables also extend lifespan, and 4) whether this gene is a novel regulator of lifespan through effect on TORC1.

Public Health Relevance

Aging persists in the human population and contributes to age-associated disorders. However, the root causes of age-associated declines in cellular process remain unsolved. Our studies in yeast have uncovered a novel genome factor that promotes lifespan extension through a conserved mechanism of aging. Analysis of the mechanism underlying lifespan control by the newly identified aging factor will extend our understanding aging and provide a foundation for developing interventions that extend lifespan in the human population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AG055326-03
Application #
9614844
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Velazquez, Jose M
Project Start
2017-01-01
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032