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Recent Research into Klotho and Aging

The klotho gene can be manipulated to either reduce or somewhat extend life in mice and nematode worms, but has not been well studied in comparison to some other aspects of longevity-associated biology. Researchers are still mapping out relationships and discovering associations; this stage of the investigation of a gene and its role in our biological machinery might last for decades, conducted at a slow and methodical pace.

Here are some examples of more recent studies involving klotho, starting with evidence that klotho extends life in nematodes by acting through two known longevity mechanisms. We would expect to see a lot of this sort of thing - that a new longevity-associated gene works by indirectly manipulating one of the known processes that can affect life span.

Klotho exerts anti-aging properties in mammals in two different ways. While membrane-bound Klotho, which is primarily expressed in the kidney, acts as an obligate co-receptor of FGF23 to regulate phosphate homeostasis, secreted Klotho [inhibits] Insulin/IGF1 signalling. ... Klotho appears to crosstalk with both FGF and Insulin/IGF1/FOXO pathways to exert anti-aging properties in C. elegans.

In comparison to this, there is the oxidative stress viewpoint: that klotho confers resistance to the damage caused by free radicals such as reactive oxygen species, and therefore we would expect extended life to result under the free radical theory of aging.

Reactive oxygen species (ROS) and elevated levels of p38 MAPK activity accelerate physiological aging. This emphasizes the importance of understanding the molecular mechanism(s) that link ROS production to activation of the p38 mediated promotion of aging, longevity, and resistance to oxidative stress. We examined Klotho(-/-) (elevated ROS) and Klotho overexpressing mice (low ROS and resistance to ROS) ... We propose [that] increased longevity by Klotho overexpression is linked to suppression [of] p38 MAPK activity

This view is not incompatible with the first - they are looking at different layers or areas of biochemistry. Metabolism is ferociously complex, which is one of the challenges facing those who want to safely alter its operation in humans to slow aging.

Klotho doesn't exist in a vacuum of course. Like all parts of our biochemistry, its level of expression may be altered by circumstances and other changes taking place in our biological machinery - which in turn means that it is causing further alterations. All of which has made it historically challenging to figure out where the end of the string lies. What is cause, what is contributer, and what is irrelevant - answers which may turn out to be very different for the same process when conducted under only slightly different circumstances. The study of metabolism is not for the faint of heart.

As an example, you'll find altered klotho levels showing up in this research on how to at least slow mitochondrial contributions to aging - a familiar theme for regular readers.

Angiotensin II blockade: a strategy to slow aging by protecting mitochondria?

Protein and lipid oxidation - mainly by mitochondrial reactive oxygen species (mtROS) - was proposed as a crucial determinant of life- and healthspan.

Angiotensin-II enhances ROS production [and] stimulates mtROS production, which depresses mitochondrial energy metabolism. In rodents, renin-angiotensin system blockade (RAS-bl) increases survival, and prevents age-associated changes. RAS-bl reduces mtROS, and enhances mitochondrial content and function. This suggests that angiotensin-II contributes to the aging process by prompting mitochondrial dysfunction.

...

Caloric restriction - an age-retarding intervention in humans and animals - and RAS-bl, display a number of converging effects, i.e., they delay the manifestations of hypertension, diabetes, nephropathy, cardiovascular disease and cancer; increase body temperature; reduce body weight, plasma glucose, insulin and insulin-like growth factor-I; ameliorate insulin sensitivity; lower protein, lipid, and DNA oxidation, and mitochondrial H(2)O(2) production, and increase UCP-2 and sirtuin expression.

Other potential mechanisms that may underlie RAS-bl's mitochondrial benefits are TGF-beta downregulation and upregulation of Klotho and sirtuins.

Quite a list there at the end - it's worth remembering that calorie restriction moves near all biochemical processes studied to date in a beneficial direction for your long term health. But how to pick out what gene and protein is doing what when faced with an array of changes that affect near every biological subsystem known to touch on aging? It's a tough business to be in.

Comments

Looking at Protein intake by quintiles and the lifespan and disease rates provides clear evidence that protein restriction is as effective as Calorie Restriction.

Protein intake differances between men and women explain much if not all of the lifespan differances.

We need research for optimal protein intake for older people.

How many proposals to the NIA has fight aging helped submit?

A group effort to have substances tested would be a positive step.

Beyond drugs like Rapamycin are foods high in chemicals like Glycerol, Triacetin, Mannoheptulose, Trehalose, and more with the potential to increase our healthy life span and decrease our medical cost per person per year.

Posted by: Eric Anderson at September 26th, 2010 5:59 PM

Klotho protein deficiency and aging
"It is of interest that both α-kl−/− mice and FGF23 knockout mice show similar symptoms resembling human aging.1,30,34 Both mice also show aberrant renal phosphate re-absorption and enhanced 1,25(OH)2D3 synthesis, leading to the elevation of serum concentrations of phosphate, 1,25(OH)2D3, and calcium. In wild-type mice, administered vitamin D3 alters several gene expressions, including the upregulation of CYP24A1 and vitamin D receptor, and downregulation of CYP27B1. In contrast, these gene responses were not observed in α-kl−/− mice and restriction of vitamin D3 improved abnormal phenotypes of α-kl−/− mice. α-Klotho protein is shown to function in the negative feedback regulation of vitamin D3 synthesis by downregulation of CYP27B1.35,36 These observations indicated that abnormal vitamin D3 metabolism is the main cause of aging phenotypes.35,36"

Plasma vitamin D and mortality in older men: a community-based prospective cohort study

"An approximately 50% higher total mortality rate was observed among men in the lowest 10% (98 nmol/L) of plasma 25(OH)D concentrations compared with intermediate concentrations"

That mortality increasing highest level of 98mnl/l or 40ng/ml is less than certain 'experts' are proposing as a minimum.

Posted by: Lere at October 18th, 2010 5:15 AM

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