Tuesday, June 10, 2014

Tonics for a long life?

I've recently come across two articles relevant to life extension (work done with mice and worms, to be sure, but a human who reads these papers might well be trying to get their hands on some of the stuff described to give it a try!). Dubai et al. report their work on Klotho, an aging regulator that, when overexpressed, extends lifespan in mice and nematode worms, and, when disrupted, accelerates aging phenotypes. (A lifespan expanding human variant of the KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers.) Here is their summary:
Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages.
And, Ye et al. have done a screen, using nematodes, of over 1200 drugs active on human cells, including drugs approved for human use, finding ~60 that increase C. elegans lifespan up to 43%. They mainly act on proteins that function in signaling pathways between cells relevant to oxidative stress resistance - hormone or neurotransmitter receptors, particularly those for adrenaline and noradrenaline, serotonin, dopamine, histamine, and serotonin. This suggests and narrows down a list of drugs that might be tested for life extension in mammals.
One goal of aging research is to find drugs that delay the onset of age-associated disease. Studies in invertebrates, particularly Caenorhabditis elegans, have uncovered numerous genes involved in aging, many conserved in mammals. However, which of these encode proteins suitable for drug targeting is unknown. To investigate this question, we screened a library of compounds with known mammalian pharmacology for compounds that increase C. elegans lifespan. We identified 60 compounds that increase longevity in C. elegans, 33 of which also increased resistance to oxidative stress. Many of these compounds are drugs approved for human use. Enhanced resistance to oxidative stress was associated primarily with compounds that target receptors for biogenic amines, such as dopamine or serotonin. A pharmacological network constructed with these data reveal that lifespan extension and increased stress resistance cluster together in a few pharmacological classes, most involved in intercellular signaling. These studies identify compounds that can now be explored for beneficial effects on aging in mammals, as well as tools that can be used to further investigate the mechanisms underlying aging in C. elegans.

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