Identification and Application of Gene Expression Signatures Associated with Lifespan Extension

Tyshkovskiy, Alexander; Bozaykut, Perinur; Borodinova, Anastasia A.; Gerashchenko, Maxim V.; Ables, Gene P.; Garratt, Michael; Khaitovich, Philipp; Clish, Clary B.; Miller, Richard A.; Gladyshev, Vadim N.

doi:10.1016/j.cmet.2019.06.018

Cited by 138 publications

(155 citation statements)

References 151 publications

(237 reference statements)

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“…Enhanced bioavailability and/or production capacity of endogenous H2S, particularly via CGL activity, has only recently been recognized as a common phenomenon and proposed mechanisms of action for dietary, genetic, and pharmacological models of longevity and healthy aging across evolutionary boundaries Kabil et al, 2011a;Tyshkovskiy et al, 2019). However, the molecular mechanisms underlying many of the pleiotropic cellular, physiological, and systemic benefits of H2S, particularly and in the context of diet and aging, have remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Lack of CGL expression and/or activity is attributed to hypertension (Yang et al, 2008), neurodegeneration (Paul et al, 2014), and the inability to properly respond to dietary and endocrine cues (Hine et al, 2015;Ishii et al, 2010;Kabil et al, 2011a;Longchamp et al, 2018;Nakano et al, 2015). Remarkably, it was recently found that increased CGL expression in liver is a hallmark of numerous dietary, genetic, hormonal, and pharmaceutical mouse models of extended lifespan and may serve as a molecular biomarker associated with longevity (Tyshkovskiy et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Dietary restriction transforms the protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

Bithi

Link

Wang

et al. 2019

Preprint

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One Sentence Summary: Dietary restriction altered the tissue-specific enrichment of sulfhydrated proteins and their downstream signaling pathways in liver, kidney, skeletal muscle, brain, heart, and plasma that was partly dependent on the hydrogen sulfide producing enzyme cystathionine γ-lyase.Abstract: Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein sulfhydration (R-SSnH). Despite the known importance of sulfhydration on relatively few identified proteins, tissue-specific sulfhydrome profiles and their associated functions are not well characterized, specifically under conditions known to modulate H2S production. We hypothesized that dietary restriction (DR), which increases lifespan and boosts endogenous H2S production, expands functional tissue-specific sulfhydromes. Here, we found that 50% DR enriched total sulfhydrated proteins in liver, kidney, muscle, and brain but decreased these in heart of adult male mice. DR promoted sulfhydration in numerous metabolic and aging-related pathways. Mice lacking the H2S producing enzyme cystathionine γ-lyase (CGL) had decreased liver and kidney protein sulfhydration and failed to functionally augment their sulfhydrome in response to DR. Overall, we defined tissue-and CGLdependent sulfhydromes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dietary restriction transforms the protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

Bithi

Link

Wang

et al. 2019

Preprint

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“…Additionally, multiple lifespan extending compounds, including 17α-E2, exhibit similar modifications in liver function [27]. In all, recent studies by several independent laboratories strongly indicate that the lifespanextending effects of 17α-E2 are at least associated with, if not dependent on, metabolic improvements.…”

Section: Introductionmentioning

confidence: 88%

“…We have found that 17α-E2 administration reduces food intake and regional adiposity in combination with significant improvements in a multitude of systemic metabolic parameters in both middle-aged obese and old male mice without inducing deleterious effects [22][23][24]. Other groups have also determined that lifelong administration of 17α-E2 beneficially modulates metabolic outcomes, including glucose tolerance, mTORC2 signaling, and hepatic amino acid composition and markers of urea cycling, which were reported to be dependent upon the presence of endogenous androgens [25,26].Additionally, multiple lifespan extending compounds, including 17α-E2, exhibit similar modifications in liver function [27]. In all, recent studies by several independent laboratories strongly indicate that the lifespanextending effects of 17α-E2 are at least associated with, if not dependent on, metabolic improvements.Despite the mounting evidence demonstrating that 17α-E2 improves numerous health parameters, the signaling mechanism(s) and primary tissues through which 17α-E2 elicits these benefits remain unknown.Although 17α-E2 is a naturally-occurring enantiomer to 17β-estradiol (17β-E2), it has been postulated that 17α-E2 signals through a novel uncharacterized receptor [28][29][30][31] as opposed to classical estrogen receptors alpha (ERα) and beta (ERβ); which is due to 17α-E2 having significantly reduced binding affinity to ERα and ERβ as compared to 17β-E2 [32][33][34][35].…”

mentioning

confidence: 99%

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Mann

Hadad

Nelson-Holte

et al. 2020

Preprint

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Aging is the greatest risk factor for most chronic diseases. Metabolic dysfunction underlies several chronic diseases, which are further exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging processes, although compliance issues remain paramount due to adverse effects on quality of life.17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanism by which 17α-E2 elicits benefits remain unknown, which has led speculation that an uncharacterized receptor is involved. Herein, we show that 17α-estradiol and 17β-estradiol elicit similar genomic binding and transcriptional activation of ERα and that the ablation of ERα in male mice completely attenuates the beneficial effects of 17α-estradiol. Our findings also suggest that 17α-E2 acts primarily through the liver and/or hypothalamus to elicit benefits, and that 17α-E2 also improves metabolic parameters in male rats. Collectively, these data suggest ERα is a relevant drug target for mitigating chronic diseases in male mammals. KEYWORDS17α-estradiol, aging, estrogen receptor, hypothalamus, liver, metabolism, obesity Aging is the leading risk factor for most chronic diseases, many of which are associated with declines in metabolic homeostasis [1]. Metabolic detriments associated with advancing age are further exacerbated by obesity [2,3], which has risen substantially in the older population (> 65 years) over the past several decades [4,5]. Moreover, obesity in mid-life has been shown to accelerate aging mechanisms and induce phenotypes more commonly observed in older mammals [6][7][8][9][10][11][12]. These observations have led many to postulate that obesity may represent a mild progeria syndrome [13][14][15][16][17]. Although it is well established that dietary interventions, including calorie restriction, can reverse obesity-related metabolic sequelae, many of these strategies are not well tolerated in older patients due to concomitant comorbidities [2,18]. Compliance issues across all age groups also remain a paramount hurdle due to calorie restriction adversely affecting mood, thermoregulation, and musculoskeletal mass [19]. These adverse health outcomes demonstrate the need for pharmacological approaches aimed at curtailing metabolic perturbations associated with obesity and aging.17α-estradiol (17α-E2) is one of the more recently studied compounds to demonstrate efficacy for beneficially modulating obesity-and age-related health outcomes. The NIA Interventions Testing Program (ITP) found that long-term administration of 17α-E2 extends median lifespan of male mice in a dose-dependent manner [20,21]. Our group has been exploring potential mechanisms by which 17α-E2 may improve healthspan and extend lifespan in a sex-specific manner. We have found that 17α-E2 administration reduces food intake and regional adiposity in combination with significant improvements in a multitude of systemic metabolic parameters in both middle-aged obese and old male mice without inducing deleterious effects [22][23...

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“…Older age is the greatest risk factor for the development of most chronic diseases (1). Accordingly, 98 recent large-scale 'omics' studies have aimed to characterize novel genes and biological pathways 99 that influence aging, and to identify related interventions (e.g., pharmaceutical compounds, exercise, 100 nutrition) that increase longevity and healthspan (2,3). Indeed, advances in transcriptomics (e.g., 101 RNA-seq) have led to important insight on many genes and pathways linked with 'the hallmarks of 102 aging' and broader health outcomes (4).…”

Section: Healthy Aging Interventions Reduce Non-coding Repetitive Elementioning

confidence: 99%

Healthy aging interventions reduce non-coding repetitive element transcripts

Wahl

Cavalier

Smith

et al. 2020

Preprint

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Transcripts from non-coding repetitive elements (RE) in the genome may be involved in aging. However, they are often ignored in transcriptome studies on healthspan and lifespan, and their role in healthy aging interventions has not been characterized. Here, we analyze RE in RNA-seq datasets from mice subjected to robust healthspan- and lifespan-increasing interventions including calorie restriction, rapamycin, acarbose, 17-α-estradiol, and Protandim. We also examine RE transcripts in long-lived transgenic mice, and in mice subjected to high-fat diet, and we use RNA-seq to investigate the influence of aerobic exercise on RE transcripts with aging in humans. We find that: 1) healthy aging interventions/behaviors globally reduce RE transcripts, whereas aging and age-accelerating treatments increase RE expression; and 2) reduced RE expression with healthy aging interventions is associated with biological/physiological processes mechanistically linked with aging. Thus, RE transcript dysregulation and suppression are likely novel mechanisms underlying aging and healthy aging interventions, respectively.

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Identification and Application of Gene Expression Signatures Associated with Lifespan Extension

Cited by 138 publications

References 151 publications

Dietary restriction transforms the protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

Dietary restriction transforms the protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Healthy aging interventions reduce non-coding repetitive element transcripts

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