Genetic insight into senescence from the Drosophila brain

Project Summary
Cellular senescence is a state triggered by wound healing or for tumor suppression, whereby cells arrest and
express inflammatory and cytokine genes 1,2. Although of benefit acutely, senescent cells contribute to tissue
decline due to the unabated stimulation of inflammation, proteolysis and cytokine signaling. A number of studies
have shown that that mitigating or eliminating senescent cells can not only mitigate disease pathologies, but also
promote a healthy lifespan in normal mice 1,3,4. Senescence can be challenging to study in vivo, given the small
number of cells and difficulty identifying them. However, greater understanding of senescence in vivo would allow
critical insight into manipulating senescence and both the benefits and drawbacks of senescence. We recently
identified cells in the Drosophila brain that naturally become senescent with age 5. These cells activate the AP1
transcription factor complex, a recently defined pioneer factor for senescence 6. Detailed analysis revealed that
the AP1 pathway becomes active in a subset of glia with age, and AP1+ cells have hallmarks of senescence
including a transcriptional signature of the senescence-associated secretory phenotype (SASP). We identified
that one activator for senescence in the fly is neuronal mitochondrial decline. We also were able to mitigate
senescence by dampening AP1 activity in glia, which had beneficial but also deleterious effects: lifespan and
climbing ability were improved, but the brain was more susceptible to oxidative damage and neuronal decline
proceeded. We propose here to take advantage of the powerful genetics of Drosophila with screens to uncover
players that, when knocked down in neurons or in glia, will modulate senescence onset and associated hallmarks
including age-associated decline of the brain. In Aim 1 we will selectively knockdown genes in adult neurons
and screen for advanced senescence. In Aim 2 we will perform a complementary screen, now knocking down
genes in glia to screen for advanced senescence. This screen should also reveal players of communication
between the neurons and glia in the generation and maintenance of senescent cells and their activities. Given
the limited systems where one can apply genetic tools to uncover molecular insight in vivo into senescence, and
the vast potential and impact of Drosophila genetic screens, this approach promises to provide vast new
understanding into pathways critical for driving senescence, aging of the brain and age-associated disease
onset.

Grant Number: 1R21AG095657-01
NIH Institute/Center: NIH
Principal Investigator: Nancy Bonini