The goal of my research program is to understand and manipulate the molecular pathways that promote the healthy survival of an organism. Our hypothesis is that many of the signaling pathways that impinge on the aging process do so, in part, by directly modulating the molecular machinery that assists in protein folding and maintenance of their functional conformations, from both a static and dynamic perspective. My research group is divided into two related research clusters: one focuses on the identification of the molecular pathways of aging, and the second investigates how these pathways affect the fidelity of protein homeostasis, with an emphasis on diseases associated with protein misfolding. Our research cycles between initial discoveries in the wormCaenorhabditis elegans and more complex analyses in the mouse.
The discovery of genetic pathways that can be predictably altered to regulate the aging process led to a revolution in the field of molecular gerontology, moving it from a purely descriptive scientific endeavor to one of mechanistic, hypothesis-based experiments. This emergence resembles the early time period of developmental genetics when scientists first discovered that embryonic pattern formation is determined by the temporal ordering of early-acting genetic programs. In this regard, aging can be viewed as a series of developmental stages during which receptive cues initiate a sequence of molecular events that ultimately lead to the execution of evolutionarily engrained aging processes.
The identification of genetic circuits that regulate aging has suggested the realistic possibility of creating therapeutic strategies that can target these molecular pathways to modulate both the aging process and age-associated diseases. This translational component to aging research is a bold notion that has brought much excitement to the field. However, our focus remains not on the potential extension of human longevity but on the modulation of the aging process to retard or even prevent age-onset diseases, particularly neurodegenerative diseases.
Within a genetically tractable model organism with a short life span such as C. elegans, aging is often measured as the total life span of a population of age-synchronized animals. Despite the large number of mutations that influence aging, however, most of these longevity genes can be grouped into one of three distinct pathways that regulate life span in worms, flies, and mice. Reduced insulin signaling, dietary intake, or rates of mitochondrial respiration can increase life span via signaling mechanisms that are genetically regulated and independent of one another. All three pathways regulate longevity in C. elegans and in mice, suggesting an evolutionarily conserved mechanism for the determination of life span. Evidence for the independence of these pathways comes from three sets of observations.
First, simultaneous manipulation of more than one of these three pathways results in longer life span than is seen through the manipulation of a single pathway. Second, the temporal requirements during the life cycle for each pathway are separable: loss of insulin signaling during adulthood regulates life span, mitochondrial respiration must be lost during early development to extend longevity, and dietary restriction appears capable of being imposed at any time during the life span to increase longevity. Most compelling, transcription factors that are an absolute requirement for one pathway (such as DAF-16/FoxO for insulin signaling and PHA-4/Foxa for diet restriction) are dispensable for the longevity effects of other pathways. Therefore, within the genetic pathways of aging, DAF-16/FoxO and PHA-4/Foxa, members of a conserved family of winged-helix transcription factors known as forkhead proteins, appear to constitute the beginning of a conserved "forkhead code" for longevity assurance.
Late-onset human neurodegenerative diseases, including Alzheimer's (AD), Huntington's, Parkinson's, and the prion maladies, are genetically and pathologically linked to aberrant protein aggregation. AD, the most common type of dementia, is typically sporadic; however, rare mutations in several genes confer early onset. Release of the aggregation-prone peptides Aβ1–40 and Aβ1–42 by endoproteolysis of the amyloid precursor protein (APP) is associated with AD through an unknown mechanism that appears to be associated with Aβ aggregation. Typically, individuals who carry AD-linked mutations present with clinical symptoms during their fifth or sixth decade, while sporadic cases appear after the seventh decade. Although aggregation-mediated neurodegeneration emerges late in life, it is unclear whether this late onset is mechanistically linked to the aging process.
Five unanticipated results from our work provide insights into the coupling of the aging process to toxic protein aggregation. First, reduced insulin/insulin growth factor-1 (IGF-1) signaling greatly suppresses the toxic effects of human Aβ1–42 in worms, indicating that signals associated with the aging program can also decrease cytotoxicity associated with Aβ1–42 aggregation. Second, the insulin/IGF-1 pathway regulates two key transcription factors, DAF-16 and HSF-1, which together influence aggregation and toxicity. Third, the formation of high-molecular-weight (MW) aggregates can be uncoupled from toxicity, as DAF-16 and HSF-1 appear to have opposing functions in the detoxification of Aβ1–42. DAF-16 regulates a transcriptome whose products convert low-MW toxic aggregates into high-MW aggregates, while the HSF-1 transcriptome efficiently takes aggregates apart, allowing monomers that are proteolyzed, in part by the proteasome. The HSF-1 transcriptome appears to encode the primary pathway for aggregate detoxification. Fourth, a small membrane-associated Aβ quaternary structure, perhaps one made of trimeric building blocks, correlates with cytotoxicity. Fifth, translation of our work into a bona fide mouse model of AD confirms the important role that insulin/IGF-1 signaling plays in the onset of AD. The latter exciting result implicates intracellular protective pathways in amelioration of a disease that is considered by most to be an extracellular misfolding disorder.
The greatest risk factor for nearly all neurodegenerative diseases is aging. Our central hypothesis is that continual production of aggregation-prone proteins eventually leads to age-onset proteotoxicity and to disease. To understand the molecular mechanisms that prevent proteotoxicity during early life and become compromised with age, we will expand on our results inC. elegans. These results point toward a protective disaggregation activity and a protective aggregation activity that are regulated by the aging program. In the next phase of our work, we will focus on determining whether the same protective mechanisms exist in mammals. Finally, we will broaden our research to determine whether other pathways of aging also regulate age-onset proteotoxicity in simple and more complex model systems such as C. elegans and mice.
Our goal is to identify the core genetic regulators of longevity and survival of an organism. Once we identify a pathway, we investigate its mechanistic basis and requirements. From this work, we question how these pathways can alter the protein homeostasis networks to circumvent many age-related diseases, primarily those of neuronal origin. My lab has transitioned into analysis in the mouse while keeping our complementary focus on the genetics and biochemistry of the worm. We anticipate that this synergy will provide relevant information for human disease.
As of May 30, 2012