Altered expression of the Cdk5 activator-like protein, Cdk5α, causes neurodegeneration, in part by accelerating the rate of aging [head]. Drosophila melanogaster

Aging is the greatest risk factor for neurodegeneration, but the connection between the two processes remains opaque. This is in part for want of a rigorous way to define physiological age, as opposed to chronological age. Here, we develop a comprehensive metric for physiological age in Drosophila, based on genome-wide expression profiling. We applied this metric to a model of adult-onset neurodegeneration, increased or decreased expression of the activating subunit of the Cdk5 protein kinase, encoded by the gene Cdk5α, the ortholog of mammalian p35. Cdk5α-mediated degeneration was associated with a 27-150% acceleration of the intrinsic rate of aging, depending on the tissue and genetic manipulation. Gene ontology analysis and direct experimental tests revealed that affected age-associated processes included numerous core phenotypes of neurodegeneration, including enhanced oxidative stress and impaired proteostasis. Taken together, our results suggest that Cdk5α-mediated neurodegeneration results from accelerated aging, in combination with cell-autonomous neuronal insults. These data fundamentally recast our picture of the relationship between neurodegeneration and its most prominent risk factor, natural aging. Overall design: 82 Drosophila samples representing two tissue types (head, thorax), four ages (3 Days, 10 Days, 30 Days, 45 Days), four genotypes (control, p35-null, p35-OE, rescue), and two batches (batch 1, batch 2) with one technical replicate sample run between batches.