The Long and Short of It: Insulin Trumps Telomeres in Organismal Aging

The progressive shortening of telomeres, those DNA caps that protect the ends of chromosomes, limits the lifespan of dividing cells. When telomeres get too short, the cells stop replication and senesce. But these guardians of genome integrity do not dictate aging in non-dividing cells, according to a new study from Jan Karlseder and colleagues at the Salk Institute in San Diego appearing online in PLoS Genetics. Karlseder’s work on telomere length and longevity in C. elegans shows that other factors, including the activity of insulin signaling pathway, are more important than telomere length in organismal aging.

The observations in worms could be relevant to neurons and other non-dividing cells in higher animals, and in fact another study, this one clinical, indicates the importance of keeping insulin signaling under control for healthy aging in humans. In that study, Mark Fishel and colleagues show that administering insulin to healthy volunteers acutely increases inflammatory markers and β-amyloid in the CNS. The study, now available online in the Archives of Neurology, provides a direct mechanistic link between high insulin levels, like those seen in insulin-resistant diabetics, and neurological aging in the form of increased risk of AD.

To ask how non-dividing cells keep time, Karlseder and co-workers took advantage of the nematode C. elegans, a model organism whose adult form contains exclusively non-dividing cells. First author Marcela Raices and colleagues measured telomere size in clonal populations of worms, and found that the average length varied among clones, and that the trait of long or short telomeres was conserved over generations. Different strains of C. elegans displayed widely different characteristic telomere length, but there was no correlation between length and longevity of the strains. Unlike in human replicating cells, telomere length did not diminish with aging, and was not reduced by stress. Mutations or knockdowns in an insulin-like signaling pathway that made the worms live longer or die more quickly had no effect on telomere length.

By all these measures, then, the worm studies clearly separate replicative aging due to telomere shortening and aging of postmitotic cells, and show that the latter is important for overall lifespan. “Telomere length and lifespan can be uncoupled in a postmitotic setting, suggesting separate pathways for replication-dependent and independent aging,” they write, adding that other genetic pathways, such as the insulin/IGF-1 pathway, are presumably required for the proper aging of postmitotic cells. The message for would-be developers of anti-aging drugs is that it’s not enough to shoot for telomere maintenance, but meddling with these other pathways will be necessary as well to ensure not just a longer life, but disease-free aging.

Overactive insulin production in humans, often seen in type II diabetes, is associated with a number of ills, including runaway inflammation and an increased risk of AD (see ARF live discussion). To directly test the idea that peripheral insulin could incite inflammation in the CNS, Fishel and colleagues infused 16 healthy older adults with insulin to mimic the levels seen in insulin-resistant diabetics, while maintaining blood glucose levels. The researchers observed reliable elevation in CSF insulin levels, and the inflammatory cytokines IL-1α and β, IL-6, TNFα, and F2-isoprostane. The investigators had previously reported that in this group of adults, insulin administration increased CNS Aβ42 in an age-dependent way, and here they show plasma Aβ42 is also increased, and that the extent of rise was larger in patients with higher BMI. Insulin administration also affected other molecules associated with Aβ metabolism and AD risk, such as transthyretin, ApoE, and norepinephrine.

Based on their results, Fishel et al. propose a model where hyperinsulinemia can raise plasma Aβ42, and kick off a vicious cycle of Aβ brain accumulation and inflammation, leading to AD. The results serve as a caution, the authors say, in the face of a steeply increasing incidence of hyperinsulinemia due to obesity and diabetes, but also could encourage the search for new strategies to treat, delay, or prevent AD.—Pat McCaffrey

Comments

  1. This paper raises several provocative issues. It also lends further support to those who believe that the secondary function of telomeres is to serve as a checkpoint for uncontrolled cellular proliferation. This makes sense in tissues that continue to undergo mitosis. But it raises the question, "What is the function of telomeres in non-replicative cells?" They must have some function; what is their function and why are they there? I have an idea but would like to hear from others first.

    View all comments by Richard Bowen

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References

Other Citations

  1. ARF live discussion

Further Reading

Primary Papers

  1. Fishel MA, Watson GS, Montine TJ, Wang Q, Green PS, Kulstad JJ, Cook DG, Peskind ER, Baker LD, Goldgaber D, Nie W, Asthana S, Plymate SR, Schwartz MW, Craft S. Hyperinsulinemia Provokes Synchronous Increases in Central Inflammation and {beta}-Amyloid in Normal Adults. Arch Neurol. 2005 Aug 8; PubMed.
  2. Raices M, Maruyama H, Dillin A, Karlseder J. Uncoupling of longevity and telomere length in C. elegans. PLoS Genet. 2005 Sep;1(3):e30. PubMed.

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