Tinkering with Nematode Lifespan Proceeds Apace

There are too many methods of extending life in the nematode worm species Caenorhabditis elegans to mention them all, and too many related research papers arrive each year to note every one. To date all of these approaches involve changing the operation of metabolism in order to slow aging. The paper here is unusual for employing a combination of multiple genetic manipulations, rather than focusing on just one, but is otherwise representative of ongoing efforts to investigate aging by slowing it down in short-lived laboratory species. This sort of work will, I think, have little impact on the development of rejuvenation therapies for human use: those will arise from repairing the forms of molecular damage that causes aging, such as by selectively destroying senescent cells, rather than through alterations in metabolism that gently slow the accumulation of that damage.

Aging is a complex phenomenon influenced by multiple genetic pathways. Aging has been particularly well-studied in C. elegans, where more than 100 genes have been identified that can extend lifespan. Examples of pathways that influence C. elegans lifespan are: 1) control of cellular damage and redox state by mitochondrial activity, 2) protection from bacterial pathogenicity, 3) resistance to cellular stress, 4) caloric restriction and 5) aberrant expression of developmental control genes in old age.

Previous studies have focused on genes and pathways one at a time in order to examine the underlying mechanisms for lifespan extension. Recently, we have investigated the effects of manipulating many of these pathways simultaneously by expressing four transgenes with longevity functions in a transgenic strain. The first longevity transgene was zebrafish ucp2, which has mitochondrial uncoupling activity, a function that is absent from C. elegans. Expression of zebrafish ucp2 extended lifespan by 40% compared to a transgenic control strain. Uncoupling allows protons to leak into mitochondria without producing ATP, thus reducing inner membrane potential. A lower potential attenuates mitochondrial production of free radicals, which reduces free radicals damage accumulation during aging.

The second longevity gene was zebrafish lysozyme, lyz, which has an anti-bacterial function that is not found in C. elegans lysozymes. A strain expressing zebrafish lyz had a lifespan 30% longer than the transgenic control. Worm lifespan is limited by mild pathogenic effects from E. coli, which is used as a food source. Lysozymes degrade the bacterial cell wall and thus are key players against bacterial pathogens. Hence, introduction of a vertebrate lysozyme could extend lifespan by improving innate immunity via reduction of pathogenicity from E. coli.

The third longevity gene was hsf-1, which encodes heat shock transcription factor that induces expression of many stress-resistance genes. Overexpression of hsf-1 extended lifespan 35% compared to the transgenic control. The fourth longevity gene was aakg-2(sta2), which encodes the gamma subunit of AMP activated protein kinase. This is a regulatory signaling molecule that responds to low ATP/AMP ratios and plays a key role in stress response. The sta2 mutation in aakg-2 is a gain-of-function mutation that causes the enzyme to be constitutively active. C. elegans strains expressing aakg-2(sta2) had lifespans that were 45% longer than transgenic controls.

A transgenic strain was generated that expressed all four longevity genes: ucp-2, lyz, hsf-1 and aakg-2(sta2). This strain had a lifespan that was 130% longer than the transgenic control, which is roughly the sum of the effects from each longevity transgene expressed alone. Here, we extend our previous work by manipulating a developmental factor as a fifth component, namely knocking down the HOX co-factor unc-62 (Homothorax) in a strain expressing four longevity genes. RNAi against unc-62 in a wild-type worm has previously been shown to significantly extend lifespan (45%). The mechanism of lifespan extension via unc-62(RNAi) involves reprogramming several developmental pathways. First, unc-62(RNAi) decreases the expression of yolk proteins (vitellogenins) that aggregate in the body cavity in old age, thus reducing protein aggregation in old worms. Second, unc-62(RNAi) results in a broad increase in expression of intestinal genes that typically decrease expression with age, presumably allowing prolonged function in old age.

The quintuply-modified strain has a lifespan that is 160% longer than the transgenic control strain. Additionally, the quintuply-modified strain maintains several physiological markers of aging for a longer time than the transgenic control. Our results support a modular approach as a general scheme to study how multiple pathways interact to achieve extreme longevity.

Link: https://doi.org/10.1242/bio.027433


I really like those studies, regardless of their impact, or lack of, on human longevity. It's engineering with a purpose.

Posted by: ale at October 25th, 2017 1:49 AM

I don't think its all that complex to see what is driving aging, even if the downstream pathways are entangled and obscure. Basically the aging rate is set by metabolic rate (MTOR) and reactive oxygen species production rate (MtROS, which is also related to MtDNA stability), as well as to a lesser extent the adaptations to deal with the damage done by MTOR and MtROS, i.e. autophagy and HSPs, etc.

Interventions along these pathways are only ever going to slow aging, as Reason has mentioned many times.

Posted by: Mark at October 25th, 2017 3:27 AM

@Reason What type of rejuvenation / repair-of-damage research would you like to see in worms?

Which of the SENS areas (or hallmarks that have well-defined damage-repair strategies) actually apply to nematodes and could be studied in that model? (Not senescent cells for example.)

I would love to see 2 or 3 rejuvenation therapies applied to either worms or flies. I'm glad to at least see someone combining multiple interventions of any kind and publishing it. Sets the stage perhaps. Thanks for highlighting this.

Posted by: Karl Pfleger at October 26th, 2017 12:03 AM

@Karl Pfleger: Removal of lipofuscin would be the starting point, if someone could get that working. The attempt at using lasers was a failure, so it would have to be pharmaceutical. But I question the value of working in nematodes versus getting biomarkers of aging working in mammals. Once you are looking at amyloids and liposfuscin and cross-links, it starts to matter a lot more as to which species you are looking at, as the important compounds are very different.

Posted by: Reason at October 26th, 2017 5:13 PM
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