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Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1.

Onken B, Driscoll M - PLoS ONE (2010)

Bottom Line: Energy sensor AMPK and AMPK-activating kinase LKB1, which are activated in mammals by metformin treatment, are essential for health benefits in C. elegans, suggesting that metformin engages a metabolic loop conserved across phyla.We also show that the conserved oxidative stress-responsive transcription factor SKN-1/Nrf2 is essential for metformin healthspan benefits in C. elegans, a mechanistic requirement not previously described in mammals. skn-1, which functions in nematode sensory neurons to promote DR longevity benefits and in intestines for oxidative stress resistance lifespan benefits, must be expressed in both neurons and intestines for metformin-promoted healthspan extension, supporting that metformin improves healthy middle-life aging by activating both DR and antioxidant defense longevity pathways.In addition to defining molecular players operative in metformin healthspan benefits, our data suggest that metformin may be a plausible pharmacological intervention to promote healthy human aging.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, United States of America.

ABSTRACT
Metformin, a biguanide drug commonly used to treat type-2 diabetes, has been noted to extend healthspan of nondiabetic mice, but this outcome, and the molecular mechanisms that underlie it, have received relatively little experimental attention. To develop a genetic model for study of biguanide effects on healthspan, we investigated metformin impact on aging Caenorhabditis elegans. We found that metformin increases nematode healthspan, slowing lipofuscin accumulation, extending median lifespan, and prolonging youthful locomotory ability in a dose-dependent manner. Genetic data suggest that metformin acts through a mechanism similar to that operative in eating-impaired dietary restriction (DR) mutants, but independent of the insulin signaling pathway. Energy sensor AMPK and AMPK-activating kinase LKB1, which are activated in mammals by metformin treatment, are essential for health benefits in C. elegans, suggesting that metformin engages a metabolic loop conserved across phyla. We also show that the conserved oxidative stress-responsive transcription factor SKN-1/Nrf2 is essential for metformin healthspan benefits in C. elegans, a mechanistic requirement not previously described in mammals. skn-1, which functions in nematode sensory neurons to promote DR longevity benefits and in intestines for oxidative stress resistance lifespan benefits, must be expressed in both neurons and intestines for metformin-promoted healthspan extension, supporting that metformin improves healthy middle-life aging by activating both DR and antioxidant defense longevity pathways. In addition to defining molecular players operative in metformin healthspan benefits, our data suggest that metformin may be a plausible pharmacological intervention to promote healthy human aging.

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Metformin requires transcription factor SKN-1 to increase median lifespan, via a mechanism that acts in both ASI neurons and the intestine.A. Survival curves of skn-1(zu135) mutants raised on 0 mM and 50 mM metformin plates at 20°C. The median survival of animals raised on both 0 mM and 50 mM metformin plates is 9 days, and the survival curves are not significantly different. Pooled data from a total of two experiments show no change in median lifespan or survival curves (see Table S1G). We conclude that skn-1 is required for metformin's effect on median lifespan. B. SKN-1 localization in L4-stage wild-type animals expressing SKN-1::GFP grown on 0 mM and 50 mM metformin plates at 20°C. SKN-1 is present constitutively in the nuclei of ASI neurons [69] where it mediates the increased longevity response under dietary restriction. Under oxidative stress and with reduced insulin signaling, SKN-1 accumulates in intestinal nuclei leading to SKN-1 target gene expression [35], [69], [71]. Whereas SKN-1::GFP is not apparent in intestinal nuclei of animals raised on 0 mM metformin plates (top panel), SKN-1::GFP accumulates in intestinal nuclei (arrowheads, bottom panel) of animals exposed to 50 mM metformin. C. Survival curves of skn-1(zu135) animals expressing skn-1 isoforms from either the native skn-1 promoter (Is007[skn-1::gfp]), an ASI neuron-specific promoter (geIs9[gpa4p::skn-1b::gfp]), or an intestine-specific promoter (geIs10[ges-1p::skn-1c::gfp]), and raised on 0 mM or 50 mM metformin plates at 20°C. While expressing skn-1::gfp from the native skn-1 promoter rescues the inability of metformin to increase the lifespan of skn-1(zu135) mutants (see A) (median lifespan of skn-1(zu135); Is007[skn-1::gfp] animals raised on 0 mM or 50 mM metformin is 13 and 20 days, respectively, and metformin treatment shifts the survival curve or these animals significantly to the right, P = 0.0008 by the Log-rank test), expressing skn-1 only in the ASI neurons or only in the intestine does not. In fact, metformin has significantly detrimental effects in skn-1(zu135) mutants that express skn-1::gfp only in the ASI neurons (mean lifespan for these animals raised on 0 mM or 50 mM metformin is 18 and 13 days, respectively, and the surivival curve with metformin treatment is shifted significantly to the left, P<0.0001 by the Log-rank test). We performed each of these lifespan assays a total of three times with similar results, see Table S1G. Pooled data for skn-1(zu135) animals expressing skn-1::gfp from the native skn-1 promoter show a median lifespan increase from 16 days for animals on 0 mM metformin to 20 days for animals on 50 mM metformin (a 25% increase), with a significantly right-shifted survival curve (P<0.0001 by the Log-rank test, Table S1G). Pooled data for skn-1(zu135) mutants expressing skn-1::gfp only in the ASI neurons show a median lifespan decrease from 16 days for animals on 0 mM metformin to 13 days for animals on 50 mM metformin, with a significantly left-shifted survival curve (P<0.0001 by the Log-rank test, Table S1G). Note that in these experiments we cannot rule out that the tissue-specific expression of skn-1 driven by heterologous promoters provides the normally appropriate level of expression, and thus the negative effects in ASI and intestine must be evaluated with cautious attention to this caveat. D. Quantification of SKN-1::GFP nuclear localization. Wild-type animals expressing SKN-1::GFP display significantly higher incidences of SKN-1::GFP accumulation in intestinal nuclei vs. controls when exposed to 50 mM metformin (P<0.0001 by the Chi-square test). Strikingly, AMPK is required for this effect: 50 mM metformin does not induce nuclear SKN-1::GFP accumulation in the aak-2(ok524) mutant background. “Low” indicates very little or no SKN-1::GFP localization to intestinal nuclei; “Medium” indicates strong SKN-1::GFP localization to nuclei in the anterior and/or posterior of the intestine; “High” indicates strong SKN-1::GFP accumulation in nuclei throughout the intestine. Although 10 mM NaN3 did not trigger SKN-1::GFP nuclear localization on its own, we note that NaN3 is an oxidative stressor that has been shown to induce nuclear SKN-1::GFP accumulation at high concentrations [96]. To confirm that 50 mM metformin can induce SKN-1::GFP nuclear accumulation in the absence of NaN3, we performed these experiments with N2 Is007[skn-1::gfp;rol-6dm] animals raised from eggs on 0 mM and 50 mM metformin and observed in liquid M9 media. We again found that 50 mM metformin significantly increases SKN-1::GFP nuclear accumulation under these conditions (Fig. S3A).
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pone-0008758-g004: Metformin requires transcription factor SKN-1 to increase median lifespan, via a mechanism that acts in both ASI neurons and the intestine.A. Survival curves of skn-1(zu135) mutants raised on 0 mM and 50 mM metformin plates at 20°C. The median survival of animals raised on both 0 mM and 50 mM metformin plates is 9 days, and the survival curves are not significantly different. Pooled data from a total of two experiments show no change in median lifespan or survival curves (see Table S1G). We conclude that skn-1 is required for metformin's effect on median lifespan. B. SKN-1 localization in L4-stage wild-type animals expressing SKN-1::GFP grown on 0 mM and 50 mM metformin plates at 20°C. SKN-1 is present constitutively in the nuclei of ASI neurons [69] where it mediates the increased longevity response under dietary restriction. Under oxidative stress and with reduced insulin signaling, SKN-1 accumulates in intestinal nuclei leading to SKN-1 target gene expression [35], [69], [71]. Whereas SKN-1::GFP is not apparent in intestinal nuclei of animals raised on 0 mM metformin plates (top panel), SKN-1::GFP accumulates in intestinal nuclei (arrowheads, bottom panel) of animals exposed to 50 mM metformin. C. Survival curves of skn-1(zu135) animals expressing skn-1 isoforms from either the native skn-1 promoter (Is007[skn-1::gfp]), an ASI neuron-specific promoter (geIs9[gpa4p::skn-1b::gfp]), or an intestine-specific promoter (geIs10[ges-1p::skn-1c::gfp]), and raised on 0 mM or 50 mM metformin plates at 20°C. While expressing skn-1::gfp from the native skn-1 promoter rescues the inability of metformin to increase the lifespan of skn-1(zu135) mutants (see A) (median lifespan of skn-1(zu135); Is007[skn-1::gfp] animals raised on 0 mM or 50 mM metformin is 13 and 20 days, respectively, and metformin treatment shifts the survival curve or these animals significantly to the right, P = 0.0008 by the Log-rank test), expressing skn-1 only in the ASI neurons or only in the intestine does not. In fact, metformin has significantly detrimental effects in skn-1(zu135) mutants that express skn-1::gfp only in the ASI neurons (mean lifespan for these animals raised on 0 mM or 50 mM metformin is 18 and 13 days, respectively, and the surivival curve with metformin treatment is shifted significantly to the left, P<0.0001 by the Log-rank test). We performed each of these lifespan assays a total of three times with similar results, see Table S1G. Pooled data for skn-1(zu135) animals expressing skn-1::gfp from the native skn-1 promoter show a median lifespan increase from 16 days for animals on 0 mM metformin to 20 days for animals on 50 mM metformin (a 25% increase), with a significantly right-shifted survival curve (P<0.0001 by the Log-rank test, Table S1G). Pooled data for skn-1(zu135) mutants expressing skn-1::gfp only in the ASI neurons show a median lifespan decrease from 16 days for animals on 0 mM metformin to 13 days for animals on 50 mM metformin, with a significantly left-shifted survival curve (P<0.0001 by the Log-rank test, Table S1G). Note that in these experiments we cannot rule out that the tissue-specific expression of skn-1 driven by heterologous promoters provides the normally appropriate level of expression, and thus the negative effects in ASI and intestine must be evaluated with cautious attention to this caveat. D. Quantification of SKN-1::GFP nuclear localization. Wild-type animals expressing SKN-1::GFP display significantly higher incidences of SKN-1::GFP accumulation in intestinal nuclei vs. controls when exposed to 50 mM metformin (P<0.0001 by the Chi-square test). Strikingly, AMPK is required for this effect: 50 mM metformin does not induce nuclear SKN-1::GFP accumulation in the aak-2(ok524) mutant background. “Low” indicates very little or no SKN-1::GFP localization to intestinal nuclei; “Medium” indicates strong SKN-1::GFP localization to nuclei in the anterior and/or posterior of the intestine; “High” indicates strong SKN-1::GFP accumulation in nuclei throughout the intestine. Although 10 mM NaN3 did not trigger SKN-1::GFP nuclear localization on its own, we note that NaN3 is an oxidative stressor that has been shown to induce nuclear SKN-1::GFP accumulation at high concentrations [96]. To confirm that 50 mM metformin can induce SKN-1::GFP nuclear accumulation in the absence of NaN3, we performed these experiments with N2 Is007[skn-1::gfp;rol-6dm] animals raised from eggs on 0 mM and 50 mM metformin and observed in liquid M9 media. We again found that 50 mM metformin significantly increases SKN-1::GFP nuclear accumulation under these conditions (Fig. S3A).

Mentions: How metformin-activated AMPK exerts downstream effects to confer healthspan benefit is not known. Given our evidence that metformin induces DR-like physiology in C. elegans (Fig. 2B–E; Fig. S1), we sought to evaluate how AMPK activation and dietary restriction metabolism might be linked by testing known DR modulators. The C. elegans SKN-1 transcription factor, functionally and structurally related to mammalian Nrf transcription factors, contributes to lifespan extension via both DR and oxidative stress response pathways [35], [69], [70]. To investigate whether SKN-1 is required for metformin to increase median lifespan, we tested for metformin effects on the skn-1(zu135) mutant, which encodes truncated SKN-1 isoforms lacking DNA binding domains [35], [70]. We find that metformin no longer confers median lifespan benefit in the skn-1(zu135) background (Fig. 4A; similar results in a repeat of this experiment in Table S1G), suggesting that skn-1 plays an essential role in metformin's positive effects.


Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1.

Onken B, Driscoll M - PLoS ONE (2010)

Metformin requires transcription factor SKN-1 to increase median lifespan, via a mechanism that acts in both ASI neurons and the intestine.A. Survival curves of skn-1(zu135) mutants raised on 0 mM and 50 mM metformin plates at 20°C. The median survival of animals raised on both 0 mM and 50 mM metformin plates is 9 days, and the survival curves are not significantly different. Pooled data from a total of two experiments show no change in median lifespan or survival curves (see Table S1G). We conclude that skn-1 is required for metformin's effect on median lifespan. B. SKN-1 localization in L4-stage wild-type animals expressing SKN-1::GFP grown on 0 mM and 50 mM metformin plates at 20°C. SKN-1 is present constitutively in the nuclei of ASI neurons [69] where it mediates the increased longevity response under dietary restriction. Under oxidative stress and with reduced insulin signaling, SKN-1 accumulates in intestinal nuclei leading to SKN-1 target gene expression [35], [69], [71]. Whereas SKN-1::GFP is not apparent in intestinal nuclei of animals raised on 0 mM metformin plates (top panel), SKN-1::GFP accumulates in intestinal nuclei (arrowheads, bottom panel) of animals exposed to 50 mM metformin. C. Survival curves of skn-1(zu135) animals expressing skn-1 isoforms from either the native skn-1 promoter (Is007[skn-1::gfp]), an ASI neuron-specific promoter (geIs9[gpa4p::skn-1b::gfp]), or an intestine-specific promoter (geIs10[ges-1p::skn-1c::gfp]), and raised on 0 mM or 50 mM metformin plates at 20°C. While expressing skn-1::gfp from the native skn-1 promoter rescues the inability of metformin to increase the lifespan of skn-1(zu135) mutants (see A) (median lifespan of skn-1(zu135); Is007[skn-1::gfp] animals raised on 0 mM or 50 mM metformin is 13 and 20 days, respectively, and metformin treatment shifts the survival curve or these animals significantly to the right, P = 0.0008 by the Log-rank test), expressing skn-1 only in the ASI neurons or only in the intestine does not. In fact, metformin has significantly detrimental effects in skn-1(zu135) mutants that express skn-1::gfp only in the ASI neurons (mean lifespan for these animals raised on 0 mM or 50 mM metformin is 18 and 13 days, respectively, and the surivival curve with metformin treatment is shifted significantly to the left, P<0.0001 by the Log-rank test). We performed each of these lifespan assays a total of three times with similar results, see Table S1G. Pooled data for skn-1(zu135) animals expressing skn-1::gfp from the native skn-1 promoter show a median lifespan increase from 16 days for animals on 0 mM metformin to 20 days for animals on 50 mM metformin (a 25% increase), with a significantly right-shifted survival curve (P<0.0001 by the Log-rank test, Table S1G). Pooled data for skn-1(zu135) mutants expressing skn-1::gfp only in the ASI neurons show a median lifespan decrease from 16 days for animals on 0 mM metformin to 13 days for animals on 50 mM metformin, with a significantly left-shifted survival curve (P<0.0001 by the Log-rank test, Table S1G). Note that in these experiments we cannot rule out that the tissue-specific expression of skn-1 driven by heterologous promoters provides the normally appropriate level of expression, and thus the negative effects in ASI and intestine must be evaluated with cautious attention to this caveat. D. Quantification of SKN-1::GFP nuclear localization. Wild-type animals expressing SKN-1::GFP display significantly higher incidences of SKN-1::GFP accumulation in intestinal nuclei vs. controls when exposed to 50 mM metformin (P<0.0001 by the Chi-square test). Strikingly, AMPK is required for this effect: 50 mM metformin does not induce nuclear SKN-1::GFP accumulation in the aak-2(ok524) mutant background. “Low” indicates very little or no SKN-1::GFP localization to intestinal nuclei; “Medium” indicates strong SKN-1::GFP localization to nuclei in the anterior and/or posterior of the intestine; “High” indicates strong SKN-1::GFP accumulation in nuclei throughout the intestine. Although 10 mM NaN3 did not trigger SKN-1::GFP nuclear localization on its own, we note that NaN3 is an oxidative stressor that has been shown to induce nuclear SKN-1::GFP accumulation at high concentrations [96]. To confirm that 50 mM metformin can induce SKN-1::GFP nuclear accumulation in the absence of NaN3, we performed these experiments with N2 Is007[skn-1::gfp;rol-6dm] animals raised from eggs on 0 mM and 50 mM metformin and observed in liquid M9 media. We again found that 50 mM metformin significantly increases SKN-1::GFP nuclear accumulation under these conditions (Fig. S3A).
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pone-0008758-g004: Metformin requires transcription factor SKN-1 to increase median lifespan, via a mechanism that acts in both ASI neurons and the intestine.A. Survival curves of skn-1(zu135) mutants raised on 0 mM and 50 mM metformin plates at 20°C. The median survival of animals raised on both 0 mM and 50 mM metformin plates is 9 days, and the survival curves are not significantly different. Pooled data from a total of two experiments show no change in median lifespan or survival curves (see Table S1G). We conclude that skn-1 is required for metformin's effect on median lifespan. B. SKN-1 localization in L4-stage wild-type animals expressing SKN-1::GFP grown on 0 mM and 50 mM metformin plates at 20°C. SKN-1 is present constitutively in the nuclei of ASI neurons [69] where it mediates the increased longevity response under dietary restriction. Under oxidative stress and with reduced insulin signaling, SKN-1 accumulates in intestinal nuclei leading to SKN-1 target gene expression [35], [69], [71]. Whereas SKN-1::GFP is not apparent in intestinal nuclei of animals raised on 0 mM metformin plates (top panel), SKN-1::GFP accumulates in intestinal nuclei (arrowheads, bottom panel) of animals exposed to 50 mM metformin. C. Survival curves of skn-1(zu135) animals expressing skn-1 isoforms from either the native skn-1 promoter (Is007[skn-1::gfp]), an ASI neuron-specific promoter (geIs9[gpa4p::skn-1b::gfp]), or an intestine-specific promoter (geIs10[ges-1p::skn-1c::gfp]), and raised on 0 mM or 50 mM metformin plates at 20°C. While expressing skn-1::gfp from the native skn-1 promoter rescues the inability of metformin to increase the lifespan of skn-1(zu135) mutants (see A) (median lifespan of skn-1(zu135); Is007[skn-1::gfp] animals raised on 0 mM or 50 mM metformin is 13 and 20 days, respectively, and metformin treatment shifts the survival curve or these animals significantly to the right, P = 0.0008 by the Log-rank test), expressing skn-1 only in the ASI neurons or only in the intestine does not. In fact, metformin has significantly detrimental effects in skn-1(zu135) mutants that express skn-1::gfp only in the ASI neurons (mean lifespan for these animals raised on 0 mM or 50 mM metformin is 18 and 13 days, respectively, and the surivival curve with metformin treatment is shifted significantly to the left, P<0.0001 by the Log-rank test). We performed each of these lifespan assays a total of three times with similar results, see Table S1G. Pooled data for skn-1(zu135) animals expressing skn-1::gfp from the native skn-1 promoter show a median lifespan increase from 16 days for animals on 0 mM metformin to 20 days for animals on 50 mM metformin (a 25% increase), with a significantly right-shifted survival curve (P<0.0001 by the Log-rank test, Table S1G). Pooled data for skn-1(zu135) mutants expressing skn-1::gfp only in the ASI neurons show a median lifespan decrease from 16 days for animals on 0 mM metformin to 13 days for animals on 50 mM metformin, with a significantly left-shifted survival curve (P<0.0001 by the Log-rank test, Table S1G). Note that in these experiments we cannot rule out that the tissue-specific expression of skn-1 driven by heterologous promoters provides the normally appropriate level of expression, and thus the negative effects in ASI and intestine must be evaluated with cautious attention to this caveat. D. Quantification of SKN-1::GFP nuclear localization. Wild-type animals expressing SKN-1::GFP display significantly higher incidences of SKN-1::GFP accumulation in intestinal nuclei vs. controls when exposed to 50 mM metformin (P<0.0001 by the Chi-square test). Strikingly, AMPK is required for this effect: 50 mM metformin does not induce nuclear SKN-1::GFP accumulation in the aak-2(ok524) mutant background. “Low” indicates very little or no SKN-1::GFP localization to intestinal nuclei; “Medium” indicates strong SKN-1::GFP localization to nuclei in the anterior and/or posterior of the intestine; “High” indicates strong SKN-1::GFP accumulation in nuclei throughout the intestine. Although 10 mM NaN3 did not trigger SKN-1::GFP nuclear localization on its own, we note that NaN3 is an oxidative stressor that has been shown to induce nuclear SKN-1::GFP accumulation at high concentrations [96]. To confirm that 50 mM metformin can induce SKN-1::GFP nuclear accumulation in the absence of NaN3, we performed these experiments with N2 Is007[skn-1::gfp;rol-6dm] animals raised from eggs on 0 mM and 50 mM metformin and observed in liquid M9 media. We again found that 50 mM metformin significantly increases SKN-1::GFP nuclear accumulation under these conditions (Fig. S3A).
Mentions: How metformin-activated AMPK exerts downstream effects to confer healthspan benefit is not known. Given our evidence that metformin induces DR-like physiology in C. elegans (Fig. 2B–E; Fig. S1), we sought to evaluate how AMPK activation and dietary restriction metabolism might be linked by testing known DR modulators. The C. elegans SKN-1 transcription factor, functionally and structurally related to mammalian Nrf transcription factors, contributes to lifespan extension via both DR and oxidative stress response pathways [35], [69], [70]. To investigate whether SKN-1 is required for metformin to increase median lifespan, we tested for metformin effects on the skn-1(zu135) mutant, which encodes truncated SKN-1 isoforms lacking DNA binding domains [35], [70]. We find that metformin no longer confers median lifespan benefit in the skn-1(zu135) background (Fig. 4A; similar results in a repeat of this experiment in Table S1G), suggesting that skn-1 plays an essential role in metformin's positive effects.

Bottom Line: Energy sensor AMPK and AMPK-activating kinase LKB1, which are activated in mammals by metformin treatment, are essential for health benefits in C. elegans, suggesting that metformin engages a metabolic loop conserved across phyla.We also show that the conserved oxidative stress-responsive transcription factor SKN-1/Nrf2 is essential for metformin healthspan benefits in C. elegans, a mechanistic requirement not previously described in mammals. skn-1, which functions in nematode sensory neurons to promote DR longevity benefits and in intestines for oxidative stress resistance lifespan benefits, must be expressed in both neurons and intestines for metformin-promoted healthspan extension, supporting that metformin improves healthy middle-life aging by activating both DR and antioxidant defense longevity pathways.In addition to defining molecular players operative in metformin healthspan benefits, our data suggest that metformin may be a plausible pharmacological intervention to promote healthy human aging.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, United States of America.

ABSTRACT
Metformin, a biguanide drug commonly used to treat type-2 diabetes, has been noted to extend healthspan of nondiabetic mice, but this outcome, and the molecular mechanisms that underlie it, have received relatively little experimental attention. To develop a genetic model for study of biguanide effects on healthspan, we investigated metformin impact on aging Caenorhabditis elegans. We found that metformin increases nematode healthspan, slowing lipofuscin accumulation, extending median lifespan, and prolonging youthful locomotory ability in a dose-dependent manner. Genetic data suggest that metformin acts through a mechanism similar to that operative in eating-impaired dietary restriction (DR) mutants, but independent of the insulin signaling pathway. Energy sensor AMPK and AMPK-activating kinase LKB1, which are activated in mammals by metformin treatment, are essential for health benefits in C. elegans, suggesting that metformin engages a metabolic loop conserved across phyla. We also show that the conserved oxidative stress-responsive transcription factor SKN-1/Nrf2 is essential for metformin healthspan benefits in C. elegans, a mechanistic requirement not previously described in mammals. skn-1, which functions in nematode sensory neurons to promote DR longevity benefits and in intestines for oxidative stress resistance lifespan benefits, must be expressed in both neurons and intestines for metformin-promoted healthspan extension, supporting that metformin improves healthy middle-life aging by activating both DR and antioxidant defense longevity pathways. In addition to defining molecular players operative in metformin healthspan benefits, our data suggest that metformin may be a plausible pharmacological intervention to promote healthy human aging.

Show MeSH
Related in: MedlinePlus