Donnerstag, 29. Mai 2014

Quick Notes: Neuropeptidy Y, calorie restriction and aging (Draft)

Here's a short and unpolished intro to this topic. We're going to discuss the following article:

Sci Rep. 2014 Mar 31;4:4517. doi: 10.1038/srep04517.
A key role for neuropeptide Y in lifespan extension and cancer suppression via dietary restriction.
Chiba et al.

Sample size is this study's major weaknes
sample size WT-AL (n=48), NPY-AL (n=25), WT-CR (n=42), NPY-CR (n=24).
"As suspected from the survival curves, WT and Npy−/− mice seemed to respond differently to the DR diet in terms of lifespan extension (p = 0.0578 [Genotype × Diet])....The small numbers of mice in the longevity study also limit our conclusions."
The rule for a successful study should be 40-50 mice per group. Unfortunately, the most important groups in this study were the smallest.

A second huge problem is the lifespan (LS) of controls:
The strain used was 129S1/SvImJ or closely related. Median lifespan of their mice was ~840d, single outlier maximum LS below 1000d. A good rule is "900/1200" for healthy mice - 900 days mean LS and 1200d for 10%-survivorship. All other studies can be considered as using unhealthy or short-lived (strains of) mice.

In this particular instance, mean lifespan matches or surpasses values reported for the 129S1/SvImJ strain (approx. 820-880) (ref. 1). Maximum lifespan, on the other hand, is unacceptably low both compared to the vigorous black 6 strain as well as 129S1 mice kept by others (2). Mean lifespan of the last 20% surviving mice in a well kept colony of 129S1/SvImJ mice has been reported to be above 1000d (2).

Strain background
"A limitation of this study is the fact that the genetic backgrounds of the Npy/− (Npytm1Rpa/J, approximate to 129S1/SvImJ) and WT (129S6/SvEvTac) mice differed..."

Now, given those limitations, we can discuss the study, but the data is seriously called into question. The NPY hypothesis is sound, as we know from the introduction, but this paper does not make the most convincing case in favour of it.

Donnerstag, 1. Mai 2014

Proteostasis, Proteasomes and Aging

We are pretty sure that insufficient protein catabolism plays a role in aging (1-7). Important age-related pathologies include (extracellular) amyloidoses, inside and outside the brain, like those in Alzheimer's disease or less widely known in transthyretin amyloidosis. Intracellular aggregates include α-synuclein (AS) in the case of Parkinson's disease. In addition, intra-lysosomal protein-containing aggregates accumulate with aging, e.g. lipofuscin, or "A2E" in the retina. The interested reader is referred to reviews by Terman and Brunk (4), Rubinsztein (2), Cuervo (7) as well as the SENS-Foundation blog.

As an example of the proteostasis-aging link, enhanced autophagy is generally beneficial and associated with extended lifespan or rejuvenation (1, 2). Unfortunately, barring a few exceptional studies with specific interventions (1), most data is indirect ("rapamycin extends lifespan and also increases autophagy"), confounded (offtarget effects, generally) or of little translational relevance (lifespan extension in invertebrates).
A credible in vivo test of the "protein homeostasis hypothesis" would require that multiple inducers of autophagy extend lifespan in long-lived mice. The same goes for inducers of the proteasome, unfolded protein response, or chaperone mediated autophagy (CMA). So far, rapamycin, and perhaps calorie restriction, are the only examples of autophagy inducing interventions shown to extend lifespan in healthy rodents. I might be missing some, but there are only few in any case.

Now, a recent study (3) has made me question the importance of the proteasome compared to CMA and general autophagy. Since catabolic pathways are interlinked, evidence against the "proteasome hypothesis" weakens the "autophagy/CMA hypothesis" and is worth investigating, no matter your preferred hypothesis.