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Natural Variation Reveals the SIRT6 ...

Gigas, Jonathan M.,

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Natural Variation Reveals the SIRT6 C-Terminus as a Key Regulator of Pro-Longevity Activity /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Natural Variation Reveals the SIRT6 C-Terminus as a Key Regulator of Pro-Longevity Activity // Jonathan M Gigas.
作者:	Gigas, Jonathan M.,
面頁冊數:	1 electronic resource (167 pages)
附註:	Source: Dissertations Abstracts International, Volume: 86-01, Section: B.
Contained By:	Dissertations Abstracts International86-01B.
標題:	Biology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31329783
ISBN:	9798383198599

Natural Variation Reveals the SIRT6 C-Terminus as a Key Regulator of Pro-Longevity Activity /
Gigas, Jonathan M.,

Natural Variation Reveals the SIRT6 C-Terminus as a Key Regulator of Pro-Longevity Activity /Jonathan M Gigas. - 1 electronic resource (167 pages)

Source: Dissertations Abstracts International, Volume: 86-01, Section: B.

Aging is the process by which biological organisms decay over time, culminating in death. Lifespan is a genetically regulated trait that is selected in response to environmental pressures. Differences in that regulation across mammals have led to a 100-fold variation in maximum lifespan within this group. Many genes contribute to longevity, including those involved in DNA repair, cell metabolism, and gene expression. Sirtuins are a family of proteins that are involved in each of these processes, and in mammals Sirtuin6 (SIRT6) is a key regulator of aging. Presented here are several studies in which natural genetic diversity in mammals was leveraged to assess mechanisms of aging, with a particular focus on SIRT6.The first study was an investigation of phosphorylation of the SIRT6 C-terminal domain. It was found that phosphorylation is positively correlated with lifespan across many species, is abundantly performed by multiple kinase families, and increases the interaction between SIRT6 and PARP1 and subsequent resistance to oxidative stress.In the second study a unique SIRT6 variant allele in human centenarians was identified and assayed. It was demonstrated that this allele biases the enzyme function of SIRT6 away from deacetylation and towards mono(ADP-ribosylation), leading to improved DNA double-strand break repair in cells expressing this allele.The third study was a large-scale screen for proteins and post-translational modifications that are correlated with maximum lifespan across mammals. Conserved peptides were used to compare protein abundances across species by mass spectrometry and it was found that translational and mitochondrial proteins are negatively correlated with lifespan, while RNA-binding and chaperone proteins were positively correlated with lifespan. Unique phosphorylation sites were also found in long-lived species that antagonize the hallmarks of aging.Together, these studies represent a broad investigation into aging mechanisms using comparative biology, including both single-gene and omics-based approaches. The results of this work support the importance of maintaining genome stability, energy homeostasis, and proteostasis to support the evolution of a long life.

English

ISBN: 9798383198599Subjects--Topical Terms:

522710
Biology.
Subjects--Index Terms:

Natural genetic diversity

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520 $a Aging is the process by which biological organisms decay over time, culminating in death. Lifespan is a genetically regulated trait that is selected in response to environmental pressures. Differences in that regulation across mammals have led to a 100-fold variation in maximum lifespan within this group. Many genes contribute to longevity, including those involved in DNA repair, cell metabolism, and gene expression. Sirtuins are a family of proteins that are involved in each of these processes, and in mammals Sirtuin6 (SIRT6) is a key regulator of aging. Presented here are several studies in which natural genetic diversity in mammals was leveraged to assess mechanisms of aging, with a particular focus on SIRT6.The first study was an investigation of phosphorylation of the SIRT6 C-terminal domain. It was found that phosphorylation is positively correlated with lifespan across many species, is abundantly performed by multiple kinase families, and increases the interaction between SIRT6 and PARP1 and subsequent resistance to oxidative stress.In the second study a unique SIRT6 variant allele in human centenarians was identified and assayed. It was demonstrated that this allele biases the enzyme function of SIRT6 away from deacetylation and towards mono(ADP-ribosylation), leading to improved DNA double-strand break repair in cells expressing this allele.The third study was a large-scale screen for proteins and post-translational modifications that are correlated with maximum lifespan across mammals. Conserved peptides were used to compare protein abundances across species by mass spectrometry and it was found that translational and mitochondrial proteins are negatively correlated with lifespan, while RNA-binding and chaperone proteins were positively correlated with lifespan. Unique phosphorylation sites were also found in long-lived species that antagonize the hallmarks of aging.Together, these studies represent a broad investigation into aging mechanisms using comparative biology, including both single-gene and omics-based approaches. The results of this work support the importance of maintaining genome stability, energy homeostasis, and proteostasis to support the evolution of a long life.
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