Time to retire Klotho as an “anti-aging” factor?

The soluble protein Klotho appears to be an anti-aging factor, since mice deficient in the Klotho gene show signs of premature aging. However, the validity of Klotho-/- mutants as a model of progeria is controversial: many of the pathological features of the mutant phenotype can be attributed to hypervitaminosis D, and can be reversed by eliminating vitamin D from the diet. (Biogerontologists are generally more skeptical of progeria than increased longevity, since there are lots of ways to shorten lifespan that don’t involve bona fide accelerating of the aging process, whereas there are far fewer ways to lengthen lifespan without slowing that process down.)

Another blow against the idea of Klotho as a regulator of lifespan comes from Brownstein et al., who show that increased circulating levels of Klotho protein (pursuant to a chromosomal translocation that activates the gene) are associated with hyperparathyroidism and rickets (n.b. that the latter is a classic symptom of, wait for it, vitamin D deficiency).

This is interesting from an endocrinological standpoint because rickets is often the result of hypophosphatemia (low phosphate –> weak bones), whereas hyperparathyroidism is usually associated with hyperphosphatemia.

But from a biogerontological perspective, it’s both interesting and sad: Specifically, it’s a strike against the idea that we might be able to supplement aging mammals (like ourselves) with increased levels of Klotho in order to forestall aging. Of course, it’s possible that the very elevated levels of the protein seen in this study are totally off the charts, and that more modest doses might have a salubrious effect — but more and more, the most reasonable interpretation of the data is that Klotho is involved in mineral and vitamin metabolism in a way that doesn’t have much to do with lifespan; that the levels of Klotho are already more or less optimized (since a syndrome results from either deficiency or elevation relative to wildtype); and that the “progeria” of Klotho-/- is simply a compelling mimic of accelerated aging rather than a legitimate model of the process.