We recently identified the hypoxic response transcription factor, HIF-1, as a novel modifier of longevity and healthspan in Caenorhabditis elegans. In a study published in the journal Science, we showed that stabilization of HIF-1 by inhibiting its proteasomal degradation under normoxic conditions increases life span through a mechanism that is genetically distinct from dietary restriction and reduced insulin-like signaling, a finding that has since been independently replicated by two groups. We also showed that growth of wild type animals under hypoxia, which is sufficient to stabilize and activate HIF-1, also increases life span. Following publication of our study, the Kapahi lab reported that loss of HIF-1 increases life span under their experimental conditions. We have since determined that stabilization of HIF-1 increases life span in a temperature- independent manner, while loss of HIF-1 increases life span in a temperature-dependent manner. Unlike life span extension from activation of HIF-1 in normoxia, life span extension from deletion of HIF-1 or hypoxia requires the FOXO-family transcription factor DAF-16. Here we propose to further define the mechanisms by which HIF-1 modulates longevity and healthspan in C. elegans, both as a pro- and anti-longevity factor.
In Specific Aim 1, we will (1) further define the experimental conditions under which deletion of HIF-1 can increase life span and determine whether healthspan is also extended under these conditions, (2) test the hypothesis that DAF-16 is activated by loss of HIF-1 or by hypoxia using chromatin immunoprecipitation to determine whether DAF-16 is localized to known or novel target genes, and (3) determine how DAF-16 becomes relocalized to the nucleus in response to loss of HIF-1 or hypoxia by using mass spectrometry to quantify known and novel post-translational modifications of DAF-16 in response to these interventions.
In specific Aim 2, we will (1) use RNAi knock-down mRNAs that are differentially expressed in response to stabilization of HIF-1 to identify the downstream targets of HIF-1 that are involved in life span and healthspan extension when HIF-1 is stabilized under normoxic conditions and (2) determine whether these genes play a role in modulating longevity in response to other known longevity pathways.
In specific Aim 3, we will determine which cell types are involved in modulating life span and healthspan extension from stabilization of HIF-1 under normoxic conditions by generating transgenic animals expressing either (1) the VHL-1 E3 ligase which targets HIF-1 for degradation or (2) a non-degradable form of HIF-1 under promoters with known cell- type specificities and quantifying the resulting effects on longevity and measures of healthspan. HIF-1 and the hypoxic response are highly conserved from nematodes to humans and have been implicated in human diseases, most notably a variety of cancers. Thus, a better understanding of the dual role that HIF-1 can play as a modifier of life span and healthspan in nematodes will lead to new hypotheses that can be directly tested in mammals, and is likely to be directly relevant to human health and age-related disease.

Public Health Relevance

The hypoxic response is an evolutionarily conserved cellular response to reduced oxygen availability that has been implicated in several human diseases, including a variety of cancers, and which we have recently shown to regulate both life span and healthspan in Caenorhabditis elegans. The goal of this proposal is to define the mechanistic details by which the hypoxic response modulates aging and age-related disease in C. elegans, in order to understand the basic mechanisms of aging and identify potential therapeutic targets for treating age- related diseases and extending healthspan in people.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Finkelstein, David B
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University of Washington
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Leiser, Scott F; Rossner, Ryan; Kaeberlein, Matt (2016) New insights into cell non-autonomous mechanisms of the C. elegans hypoxic response. Worm 5:e1176823
Leiser, Scott F; Jafari, Gholamali; Primitivo, Melissa et al. (2016) Age-associated vulval integrity is an important marker of nematode healthspan. Age (Dordr) :
Cho, Siyoung; Cho, Miook; Kim, Juewon et al. (2015) Syringaresinol protects against hypoxia/reoxygenation-induced cardiomyocytes injury and death by destabilization of HIF-1α in a FOXO3-dependent mechanism. Oncotarget 6:43-55
Bitto, Alessandro; Wang, Adrienne M; Bennett, Christopher F et al. (2015) Biochemical Genetic Pathways that Modulate Aging in Multiple Species. Cold Spring Harb Perspect Med 5:
Pitt, Jason N; Kaeberlein, Matt (2015) Why is aging conserved and what can we do about it? PLoS Biol 13:e1002131
Leiser, Scott F; Miller, Hillary; Rossner, Ryan et al. (2015) Cell nonautonomous activation of flavin-containing monooxygenase promotes longevity and health span. Science 350:1375-8
Jafari, Gholamali; Wasko, Brian M; Tonge, Ashley et al. (2015) Tether mutations that restore function and suppress pleiotropic phenotypes of the C. elegans isp-1(qm150) Rieske iron-sulfur protein. Proc Natl Acad Sci U S A 112:E6148-57
Kaeberlein, Matt (2013) Deciphering the role of natural variation in age-related protein homeostasis. BMC Biol 11:102
Leiser, Scott F; Fletcher, Marissa; Begun, Anisoara et al. (2013) Life-span extension from hypoxia in Caenorhabditis elegans requires both HIF-1 and DAF-16 and is antagonized by SKN-1. J Gerontol A Biol Sci Med Sci 68:1135-44
Kaeberlein, Matt (2013) Longevity and aging. F1000Prime Rep 5:5

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