Impaired Insulin/IGF1 Signaling Extends Life Span by Promoting Mitochondrial L-Proline Catabolism to Induce a Transient ROS Signal

Abstract

Summary Impaired Insulin and IGF-1 Signaling (iIIS) in C. elegans daf-2 mutants extends lifespan more than two-fold. Constitutively iIIS increases mitochondrial activity and reduces reactive oxygen species (ROS) levels. By contrast, acute impairment of daf-2 in adult C. elegans reduces glucose uptake and transiently increases ROS. Consistent with the concept of mitohormesis, this ROS signal causes an adaptive response by inducing ROS-defense enzymes (SOD, catalase) culminating in ultimately reduced ROS levels despite increased mitochondrial activity. Inhibition of this ROS signal by antioxidants reduces iIIS-mediated longevity by up to 60%. Induction of the ROS signal requires AAK-2 (AMPK), while PMK-1 (p38) and SKN-1 (NRF-2) are needed for the retrograde response. IIIS upregulates mitochondrial L-proline catabolism, and impairment of the latter impairs the lifespan-extending capacity of iIIS while L-proline supplementation extends C. elegans lifespan. Taken together, iIIS promotes L-proline metabolism to generate a ROS signal for the adaptive induction of endogenous stress defense to extend lifespan.

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

“…AMPK activation is one of the main factors involved in mitohormetic lifespan extension (13,26). Although metformin is known to activate AMPK, exactly how this occurs remains elusive.…”

Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans

“…Mitochondrial ROS was detected using the mitochondrial-localized ROS sensor MitoTracker Red H 2 CMXRos as described (6). Briefly, animals were incubated in M9 buffer containing 5 μM H 2 CMXRos for 30 min, washed extensively with M9 buffer, and imaged and quantified using a Zeiss Axio Scope microscopy platform.…”

“…Interestingly, although a more detailed, side-by-side comparison is warranted, the data so far suggest that ROS can act in different ways to extend life in response to different stimuli. For example, an acute decrease in insulin/IGF-1 signaling produces a transient ROS signal that promotes life extension (6). This pathway has been reported to involve AMP kinase and altered proline metabolism, neither of which seems to be involved in the germline pathway (SI Appendix, SI Discussion).…”

“…Lifespan is also extended in response to elevated ROS levels when C. elegans is fed the glucose analog 2-deoxyglucose (4). Likewise, ROS is part of the mechanism by which TOR inhibition extends lifespan in yeast (5), and acute inhibition of the daf-2 insulin/insulin-like growth factor 1 (IGF-1) receptor extends life in C. elegans (6). ROS also plays an important role in the extension of lifespan caused by a mild inhibition of respiration in worms and flies (2,3,7).…”

Interplay between redox and protein homeostasis

“…107,108 Amplex ultrared reagent Peroxide levels can also be quantitatively accessed by incubating lysates of C. elegans with Amplex®Ul-traRed. 109 The reagent reacts with hydrogen peroxide in a 1:1 stoichiometric ratio resulting in an increased fluorescence whose emission is measured at 590 nm (excitation at 544 nm). 110 Together, these sensors offer a dynamic analysis due to their reversible oxidation and quantitative assessment of the redox state.…”