Montag, 30. Dezember 2013

Vicious Cycle Hypothesis of Mitochondrial Aging - Everything Old is New Again

There is little doubt that the classic vicious circle mitochondrial free radical "theory" of aging has been refuted. However, recent data shows that a different type of vicious circle may act on mitochondria (1) to promote organismal aging and drive sarcopenia.
Mitochondria in certain tissues are known to accumulate high levels of one and the same (= clonal) deletion. Several hypotheses have been postulated that can explain this accumulation - replication advantage, "survival of the slowest"and drift - but empirical evidence for these models has been lacking. Now the Aiken and McKenzie lab has considerably strengthened the replication advantage angle by showing a vicious circle that operates in vivo by promoting mitochondrial DNA replication. On the other hand, modeling by Kirkwood, Kowald and others (2, 3) further confirms that drift and size based replication advantage in and of themselves, and without any vicious feedback loops, operate too slowly to explain aging in short-lived species like mice.

Now, based on these three studies (1-3) we can propose a basic model for deletion accumulation that, as far as I can tell, is consistent with published data: Drift and replication advantage lead to an accumulation of OXPHOS-deficient, deletion-bearing mtDNAs until a critical threshold is reached. Then, the cell tries to compensate. Drift + Replication Advantage + Feedback Loop = fast accumulation of deletions. Aiken et al. call this feedback loop "non-adaptive program of mitochondrial biogenesis" or vicious cycle.

Two compensatory mechanisms could be maladaptive in this situation and a trigger of this vicious cycle:

Mittwoch, 11. Dezember 2013

"Vitamin D: chasing a myth?"

Hereby, I have to weaken my recommendation in favour of vitamin D supplementation, which is partly based on past analyses by Autier et al. (2) and a good risk/benefit ratio. Nowadays vitamin D still seems safe to supplement but useless.
However, the big weakness of recommendations for or against vitamin D is that the interventional studies on this topic are few and those that exist are weak. No matter how often you re-analyze garbage, the result won't improve. After so many years of research, we have not advanced much beyond the basic recommendation that vitamin D may benefit the elderly and there mainly women. Thus we absolutely have to wait for large studies to complete if we want to make strong recommendations, e.g. the VITAL and VIDAL studies.

Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including [only!] 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality. The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.

*1. Vitamin D status and ill health: a systematic review
Philippe Autier, Mathieu Boniol, Cécile Pizot, Patrick Mullie
The Lancet Diabetes & Endocrinology 1 January 2014 (Volume 2 Issue 1 Pages 76-89 DOI: 10.1016/S2213-8587(13)70165-7)

2. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.
Autier P, Gandini S.
Arch Intern Med. 2007 Sep 10;167(16):1730-7. Review.

*not read in full