The focus of this proposal is to determine how changes in chromatin with age contribute to the deleterious consequences of aging, and to develop new genetic and pharmacological interventions that extend healthy life span by effecting a more """"""""youthful"""""""" chromatin state. With age, repressive heterochromatin decreases, and both expression and mobilization of transposable elements (TEs) increase. We hypothesize that expression and mobilization of TEs contributes to aging and age-related disorders, and propose to exploit one of the cellular systems that normally suppresses TE expression and expansion, constitutive repressive heterochromatin, in order to maintain silencing of TEs and promote a longer, healthier life. We will use genome-wide approaches and interventions that affect life span, including Dietary Restriction (DR), and interventions predicted to maintain repressive heterochromatin, in order to establish the relationship between chromatin states, TE expression and transposition, and longevity. We will utilize the esiRNA RISC pathway that naturally suppresses TE expression and mobilization, in order to test directly whether repression of TE activity is an important component of longevity.
The aims of this proposal are to test the hypotheses that: (i) age-related decreases in repressive heterochromatin lead to increased TE activity;(ii) interventions that extend life span maintain repressive heterochromatin, thereby preventing increases in TE activity;(iii) interventions that increase repressive heterochromatin reduce TE activity and extend life span;and (iv) repression of TE expression and TE mobilization are important elements in longevity determination. To better understand the relationship between TE activity, the cellular mechanisms that repress it, and longevity, as well as to identify new chromatin-related pathways that can extend healthy life span, we will: (1) use RNA-seq, genomic deep-sequencing, ChIP-seq (H3K9me2, H3K9Me3, HP1) and FAIRE-seq, to test that with age there is a loss of repressive heterochromatin that is associated with increased TE expression, and that life span-extending interventions, including DR, restore repressive heterochromatin and suppress TE activity;(2) use molecular genetic manipulations known to maintain or increase repressive heterochromatin with age to test that a reduction of TE expression and mobilization will extend life span;(3) determine how the activity of the esiRNA pathway (Dicer-2, Ago2 and R2D2) is altered with age and in life span-extending interventions;and (4) use molecular genetic tools to directly alter the activity of the esiRNA pathway to affect TE expression and mobilization, in order to determine the effects of these manipulations on normal aging and on the outcome of life span-extending interventions.
The approach and experiments described in this proposal have the potential to produce results that will shed light on the relationships and molecular mechanisms linking changes in chromatin structure to alterations in gene and transposable element expression with age. Understanding of these relationships will lead ultimately to the development of interventions that can ameliorate some of the deleterious consequences of aging and age-related disorders in humans.
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