Genome-Scale Studies of Aging: Challenges and Opportunities

Abstract

Whole-genome studies involving a phenotype of interest are increasingly prevalent, in part due to a dramatic increase in speed at which many high throughput technologies can be performed coupled to simultaneous decreases in cost. This type of genome-scale methodology has been applied to the phenotype of lifespan, as well as to whole-transcriptome changes during the aging process or in mutants affecting aging. The value of high throughput discovery-based science in this field is clearly evident, but will it yield a true systems-level understanding of the aging process? Here we review some of this work to date, focusing on recent findings and the unanswered puzzles to which they point. In this context, we also discuss recent technological advances and some of the likely future directions that they portend.

Saccharomyces cerevisiae goes through distinct metabolic phases during its replicative lifespan

“…Cellular aging is a complex multifactorial process affected by an intertwined network of effectors such as protein translation, protein quality control, mitochondrial dysfunction and metabolism (Barzilai et al, 23 2012; Kennedy et al, 1994;Lagouge and Larsson, 2013;Webb and Brunet, 2014). Disentangling cause 24 and effect is a major challenge in aging research (McCormick and Kennedy, 2012). A key requisite 25 towards unraveling the causal forces of cellular aging is a comprehensive account of the concomitant 26 phenotypic changes.…”

Enhanced Longevity by Ibuprofen, Conserved in Multiple Species, Occurs in Yeast through Inhibition of Tryptophan Import

“…Hence, delaying aging therapeutically promises immense benefits to human health [2] . However, even with short-lived model organisms, the labor and time associated with unbiased screens for compounds that extend lifespan is a major obstacle [3] , [4] . To overcome this drawback, many studies focus on compounds that target pathways already implicated in aging, such as TOR signaling [5] , [6] , AMP kinase [7] , and Sirtuins [8] , [9] .…”

Author response: Protein biogenesis machinery is a driver of replicative aging in yeast

“…Understanding its driving force is the required step towards enabling interventions that might delay age-related disorders (de Magalhães et al, 2012). While this remains an unsolved problem in biology (Medawar, 1952;Mccormick and Kennedy, 2012), significant advances in the field have shown the process of aging to be malleable at both the genetic and environmental levels, indicating that it is possible for its causal elements to be dissected. The rate of aging, however, is influenced by diverse factors, including protein translation, protein quality control, mitochondrial dysfunction, and metabolism (Kennedy and Kaeberlein, 2009;Webb and Brunet, 2014;Lagouge and Larsson, 2013;Barzilai et al, 2012).…”

“…Important insights into the complex process of aging originate from research on the unicellular eukaryote Saccharomyces cerevisiae, which can produce 20-30 daughter cells before its death (Mortimer and Johnston, 1959, and see Wasko and Kaeberlein, 2014; 2014 for recent reviews). Significant contributions towards global mapping of the aging process have been demonstrated through transcriptome studies (Egilmez et al, 1989;Lin et al, 2001;Lesur and Campbell, 2004;Koc et al, 2004;Yiu et al, 2008) and genome-wide single-gene deletion lifespan measurements (reviewed in Mccormick and Kennedy, 2012). However, a major task remains to comprehensively describe the molecular changes that accompany the aging process.…”