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A comparative genetics pipeline for aging

Sutphin Lab experimental pipeline. Our formal experimental pipeline uses tools in systems and comparative genetics to: 1. generate lists of candidate aging genes from available human data, 2. apply lifespan screening in C. elegans to select the most promising candidates, 3. use molecular tools in C. elegans to build mechanistic models describing the role of selected candidate genes in aging, 4. validate these models in mice, and 5. translate validated models to develop novel clinical interventions.

The Sutphin Lab uses a combination of systems biology, comparative genetics, and molecular physiology to identify new genetic and environmental factors that are causally involved in aging and characterize their molecular role in age-associated disease. We are specifically interested in defining the range of genetic factors capable of effecting aging and understanding how they interact with one another and with variables in the environment to define longevity in a given organism. By building an increasingly accurate model of the molecular network the drives age-associated functional decline we aim to identify critical regulatory points that can be clinically targeted to extend healthy human lifespan and delay onset of age-associated disease.

Our specific approach applies a formal experimental pipeline that uses tools in systems and comparative genetics to systematically screen sets of candidate aging genes for promising targets. During his graduate and postdoctoral, Dr. Sutphin studied the genetics of aging in yeast, worms, mice, and humans. Each model system offers unique strengths and challenges. The long lifespans, high experimental costs, and ethical limitations on molecular studies in humans are complemented by the short lifespans and powerful genetic tools available in yeast or worms. However, translating results from invertebrate model systems directly to human aging is limited by evolutionary distance. Mice offer a transitional model, with powerful molecular tools that allow detailed and tissue-specific examination of aging in a mammalian context, and lifespans that are long enough to prevent large-scale aging studies, but short enough to allow targeted intervention studies. Our experimental pipeline leverages the strengths of each model system to identify and characterize novel genes and molecular processes that play a causative role in aging. This pipeline is comprised of the following steps (Figure 1):

  1. Select candidate aging gene sets through systems-level studies in mammals (preferably humans).
  2. Screen orthologs for lifespan or other age-related phenotypes using RNAi in Caenorhabditis elegans.
  3. Characterize mechanisms of lifespan extension for selected candidates in C. elegans.
  4. Validate mechanistic models and examine tissue- or disease-specific phenotypes in mice.
  5. Develop targeted interventions to slow aging or treat age-associated disease in mice.
  6. Collaborate with gerontologists to translate promising interventions to the clinic.

This pipeline is designed as a flexible experimental framework to generate hypotheses (steps 1 and 2), develop and test mechanistic models (steps 3 and 4), and translate these models into clinical interventions (steps 5 and 6). By starting with candidate genes already linked to human aging, models generated in worms and confirmed in mice are likely to be of relevance to human health. Importantly, there are numerous examples of molecular pathways originally linked to aging in invertebrate models that are now being applied to target age-associate disease in humans, such as mechanistic target of rapamycin (mTOR) signaling and sirtuins.