Samstag, 10. Januar 2015

The Tithonus Fallacy explained: The example of Nordihydroguaiaretic Acid (NDGA)

The Tithonus fallacy has been outlined elsewhere (1). Basically, it's the belief that an extension of lifespan will lead to an extension of frailty and suffering. Why this is wrong, as a rule, is obvious to a biogerontologist but not to a layperson: The diseases of aging and their underlying molecular pathologies are aging. A large extension of maximum lifespan is impossible without a delay of diseases.The 'area-under-the-curve' of health will always increase, so to say.

Border cases are substances or interventions which lead to modest changes in lifespan, particulary changes in mean lifespan. Rapamycin was assumed a potential case, but this has been refuted (2). Conceivably, lifespan may be extended somewhat by delaying a specific disease at the cost of health. Think, for instance, of a badly designed chemotherapy protocol. A substance or "longevity mutation" might also decrease the rate of aging while having some other terrible side-effects. One -- still highly speculative -- example is human dwarfism. While dwarf mice live longer than their mates, this disease is associated with (intellectual) disability and suffering in humans, yet could modestly extend lifespan in people as well (3).

Here, I would like to use a real world example based on current research (4). I'll discuss the effects of Nordihydroguaiaretic Acid (NDGA) based on recent work by Spindler. He is certainly one of the greats in the biogerontology community. The study is from his ongoing screening work, pioneering unbalanced statistical design in biogerontology to improve power and optimize use of resources.
This study is again up to highest standards with controls having a median lifespan of 983 days.

He recaps:
...the National Institute of Health Interventions Testing Program (NIH-ITP) undertook studies of the effects of NDGA on murine lifespan (10–12). They found that 2.5g of NDGA/kg diet produced a significant 12% increase in median lifespan for male mice, but not females (12). A second study found no effect on the lifespan of female mice (11). A third study censored after 70% mortality suggested that multiple NDGA doses may extend the lifespan of male mice (10). No necropsy, pathology, or toxicology results were reported, nor was food consumption reported. In Drosophila, a single dose study found a nonsignificant increase in lifespan (13).
In the new study:
B6C3F1 mice were fed AIN-93M diet supplemented with 1.5, 2.5, 3.5, or 4.5g NDGA/kg diet (1.59, 2.65, 3.71 and 4.77mg/kg body weight/day) beginning at 12 months of age. Only the 3.5mg/kg diet produced a highly significant increase in lifespan...  The drug also increased the lifespan of Drosophila, suggesting its target(s) and mechanism(s) of action may be phylogenetically conserved.
Even more worringly, the lifespan extension may be an artifact since "NDGA appears to alter either calorie absorption or utilization by the mice."

Perhaps the final nail in the coffin, NDGA is quite or at least somewhat toxic:
there was a highly or very highly significant increase in liver and lung tumors, enlarged thymuses (indicative of thymomas or lymphomas), and hemorrhage into the peritoneum ... NDGA decreased the size of liver tumors by 24% relative to those found in the control mice, suggesting that it may decrease the rate of tumor growth. However, the total mass of the tumors per mouse was unchanged, suggesting it may increase hepatic tumorigenesis

Verdict: don't eat that shit, kids!
To sum up, NDGA leads to only a small increase in median lifespan associated with liver pathology and other potential side-effects.This is more akin to the fate of Tithonus than what we see with Rapamycin or dietary restriction. I predict, this effect will appear more and more often in the literature with substances that produces such mixed and modest results like NDGA.

If you are in the business of self-experimentation, and some people are, do yourself a favour and consider calorie restriction or Rapamycin first.

What's next?
First, we'll need safe NDGA derivatives to pursue their development any further. Then let's discuss what we may see from Spindler I'm quoting my old post with links to the actual studies/blog posts discussing them:

Other interventions tested by Spindler et al....

There is also unpublished data (straight from the source) on simvastatin and simvastatin+enalapril, which seem to work in his screening test. In the same talk Spindler says, he "confirmed" the NDGA data using at least 3 different doses - top dose was toxic, however [this paper].

Everolimus (rapamycin-related) seemed to make the cut too. Oxaloacetate worked somewhat. Something "strange" worked (undisclosed substance). Other drugs already in clinical use also made it. ALT-711 failed (AGE inhibitor). Carnitine was neutral to negative(!) CoQ10 - meh! Rasagiline i.e. a Deprenyl derivative did nothing.

LExtension mix (neutral to negative), orthocore (neutral), "biostimus-??" (neutral to negative), lovaza ("it was death to these mice..actually it was not quite significant, but you decide whether you want to take it[...]..liver damage"), nicotinic acid (bad), nutraceutical combo DIY (detrimental), orthocore+pomegranate+resv+SAMe+sesame oil (toxic! / liver damage), cyperone acetate (bad liver damage).


2. J Clin Invest. 2013 Aug 1;123(8):3204-6.Rapamycin, anti-aging, and avoiding the fate of Tithonus.Richardson A1.

3. Mech Ageing Dev. 2005 Feb;126(2):305-7.Do deficiencies in growth hormone and insulin-like growth factor-1 (IGF-1) shorten or prolong longevity?Laron Z1.

4. Nordihydroguaiaretic Acid Extends the Lifespan of Drosophila and Mice, Increases Mortality-Related Tumors and Hemorrhagic Diathesis, and Alters Energy Homeostasis in Mice.
Spindler SR, Mote PL, Lublin AL, Flegal JM, Dhahbi JM, Li R.
J Gerontol A Biol Sci Med Sci. 2014 Nov 7. pii: glu190. [Epub ahead of print]

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