Aging causes decreased resistance to multiple stresses and a failure to activate specific stress response pathways

Abstract

In this work, we examine the relationship between stress resistance and aging. We find that resistance to multiple types of stress peaks during early adulthood and then declines with age. To dissect the underlying mechanisms, we use C. elegans transcriptional reporter strains that measure the activation of different stress responses including: the heat shock response, mitochondrial unfolded protein response, endoplasmic reticulum unfolded protein response, hypoxia response, SKN-1-mediated oxidative stress response, and the DAF-16-mediated stress response. We find that the decline in stress resistance with age is at least partially due to a decreased ability to activate protective mechanisms in response to stress. In contrast, we find that any baseline increase in stress caused by the advancing age is too mild to detectably upregulate any of the stress response pathways. Further exploration of how worms respond to stress with increasing age revealed that the ability to mount a hormetic response to heat stress is also lost with increasing age. Overall, this work demonstrates that resistance to all types of stress declines with age. Based on our data, we speculate that the decrease in stress resistance with advancing age results from a genetically-programmed inactivation of stress response pathways, not accumulation of damage.

Uncoupling of oxidative stress resistance and lifespan in long-lived isp-1 mitochondrial mutants in Caenorhabditis elegans

“…sod-3 and sod-5 are inducible sod genes that are normally expressed at low levels (less than 1% of total sod mRNA) in the mitochondria and cytoplasm, respectively. While it is known that the expression of these sod genes is induced under stress [21], the function of these genes is poorly understood. Deletion of either sod-3 or sod-5 has no effect on lifespan, sensitivity to juglone-induced oxidative stress, development time, fertility, defecation cycle length or rate of movement in WT worms [22, 23].…”

SKN-1-independent transcriptional activation of glutathione S-transferase 4 (GST-4) by EGF signaling

“…3 Currently, SKN-1 transcriptional activity is often indirectly assayed via a transcriptional reporter construct of the gst-4 promotor (gst-4 p ::gfp or Pgst-4::gfp; strain CL2166) which shows increased GFP levels when transcription is activated in vivo. 7,11,12,15,[19][20][21][22][23][24][25][26][27][28][29][30] By using gst-4 transcription levels as a proxy for SKN-1 activation, the problem of a low GFP signal is mitigated. Additionally, it is possible to obtain a quantitative indication of the gene's transcription levels, instead of merely being able to discriminate between cytoplasmic or nuclear localization of a transcription factor.…”

“…SKN-1 dependency can further be verified using a skn-1 null mutant background (such as the CL691 strain, gst-4 p ::gfp;skn-1(zu67) genotype), skn-1 RNAi and/or probing additional target genes. 7,11,12,15,19,20,23,[26][27][28][29][30][31][32][33] A problem arises, however, when GST-4 is used as the sole readout for SKN-1 activation, in the absence of aforementioned controls. 21,22,24,25 Based on our current observations, the interpretation of gst-4 p ::gfp fluorescence in vivo is indeed not straightforward.…”

Measuring Oxidative Stress in Caenorhabditis elegans: Paraquat and Juglone Sensitivity Assays

“…References in which this protocol was used: Van Raamsdonk and Hekimi, 2009; 2012; Van Raamsdonk et al, 2010; Cooper et al, 2015; Schaar et al, 2015; Dues et al, 2016; Machiela et al, 2016.…”

“…References in which this protocol was used: Van Raamsdonk and Hekimi, 2009; 2012; Dues et al , 2016; Schaar et al , 2015.…”