Freitag, 20. Juni 2014

Miscellaneous Lifespan Studies: Atenolol, Nutraceuticals, n3 fatty acids, SIRT, macronutrients and CR

Recently, I noticed that many study author have the bad habit of not providing full lifespan data, i.e. Kaplan–Meier curve as well as numerical mean and maximum lifespan (90th percentile survival) as well as numerical changes and statistical interpetation. That's just sloppy in my mind.
Another note: I think it's time to stop working with the venerable C57BL/6 ("black 6") strain in favour of more heterogenous and vigorous crosses, e.g. C57BL/6 x DBA/2n (5) or C57BL/6 x C3H (1).

Donnerstag, 5. Juni 2014

Noted for May (2014)

Brief summaries of current topics pertinent to health and life-extension. I am trying to cover "hot" topics, those with high impact and a random assortment of topics I find interesting.

1. In Pakistan, Nigeria and Afghanistan endemic Polio rears its ugly head again.

2. Flie researchers also have problems with artificial lifespan extension due to bad husbandry (ref. 2, chapter 5)

3. "Mice fear [the smell of] men", which could introduce artifacts in many life-span, or at least, health-span experiments. I guess. This could be particularly important in behavioral assays.
Exposure to the smell of males apparently leads to anxiety and analgesia.

4. Stem cell exhaustion (exhaustion of proliferative potential, atrophy) is one possible contributor to aging:
"Once the stem cells reach a state of exhaustion that imposes a limit ontheir own lifespan, they themselves gradually die out and steadily diminishthe body's capacity to keep regenerating vital tissues and cells, such asblood."

5. Juicing alters the glycemic profile of fruits/vegetables, but freezing is generally fine. Except with cruciferous vegetables, which, preferably, should not be frozen. (ref. 5, first 3 posts)

6. Cochrane found that Tamiflu may be almost completely ineffective and Roche made a large effort to hide the data.

7. Physical activity, i.e. wheel running, protects black 6 mice from osteoarthritis(OA) if it is initiated before the development of OA. Generally, black 6 develop OA early by 9 months of age and thus are not the best model for this disease.

1. (German link)

2. Sell, C., Lorenzini A. and Brown-Borg, H.M (eds): Life-span extension: single-cell organisms to man. Suresh, Rattan. Follow Journal Biogerontology , Volume 11. 2009.

3. Nat Methods. 2014 Apr 28. doi: 10.1038/nmeth.2935. [Epub ahead of print]
Olfactory exposure to males, including men, causes stress and related analgesia in rodents.
Sorge et al.




7. Int J Rheum Dis. 2014 Mar 18. doi: 10.1111/1756-185X.12291. [Epub ahead of print]
Lifelong physical activity and knee osteoarthritis development in mice.
Hubbard-Turner T1, Guderian S, Turner MJ.

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.

A. Results in more Detail
NPY KO almost completely abrogated the effects of CR on cancer and lifespan.
Pathology report: lymphoma and hepatic cancer, but not lung cancer, were reduced by CR. This effect was completely negated by NPY KO.

No effect on Insulin, IGF1, mTOR signalling, leptin, adiponectin, glucocorticoids or body temperature. Amazing! Could it be that none of these matter for the lifespan extension by CR? Let's not get too excited yet.

Effects on stress resistance
Liver microarray data suggests that NPY KO reduces expression of genes involve in stress resistance and particularly xenobiotic metabolism.

This was confirmed in vivo:
"We assessed survival rates of 6-month-old male mice from different experimental groups subjected to oxidative stress induced by administration of 3-nitropropionic acid, an inhibitor of mitochondrial respiratory complex II...WT-DR mice exhibited notable stress resistance in comparison to WT-AL mice, as indicated by the significantly increased survival rate (p = 0.0009 by log-rank test[...]). The DR effect was diminished in Npy/− mice (p = 0.0612 by log-rank test[...]); therefore, Npy may also be involved in the stress resistance induced by DR." [again, no significant difference due to sample size]

B. Conclusions
This study is consistent with the idea that the effect of CR is primarily dependent on NPY. It is also consistent with the idea that the effect of CR on lifespan is largely due to cancer inhibition. If this were true it would mean that pathways currently considered important are completely irrelevant (mTOR, GH/IGF, ...). Since NPY-KO abrogated the effect of CR on cancer and lifespan, but did not affect most of these biomarkers. Unfortunately, the study did not test if age-related non-cancer pathologies were decreased. It is still entirely possible that the anti-cancer effect of CR is necessary but not sufficient to extend mouse lifespan; and that this effect hinges almost entirely on NPY signalling.

Put another way: chemoprevention may be dependent upon NPY, but the anti-aging effect of CR could be independent.

Finally, this paper considerably strengthens the hypothesis that "multi-stress resistance" is central to lifespan extension, at least in rodents. The study does not completely rule out other mechanisms due to its small sample size and the peculiarities of mice as an aging model.

C. How does NPY mediate this effect?
The authors write that "Npy could act in the liver via the sympathetic nerves and the circulation.", but give no explanation and provide no citations.
Is it via circulating Neuropeptide Y? Another circulating endocrine mediator whose release is triggered by NPY? NPY as a neurotransmitter in the autonomic nervous system?

Given the effects on "stress resistance" related genes, one has to wonder if NPY and NRF2 signalling are interlinked (c.f. ref. 3 which I have not read in full).

Aging Cell. 2009 Jun;8(3):277-87. doi: 10.1111/j.1474-9726.2009.00478.x. Epub 2009 Apr 9.
Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels.
Yuan R, Tsaih SW, Petkova SB, Marin de Evsikova C, Xing S, Marion MA, Bogue MA, Mills KD, Peters LL, Bult CJ, Rosen CJ, Sundberg JP, Harrison DE, Churchill GA, Paigen B.

2. ILAR J. 2011;52(1):4-15.
Mice as a mammalian model for research on the genetics of aging.
Yuan R1, Peters LL, Paigen B.

3. Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2325-30. doi: 10.1073/pnas.0712162105. Epub 2008 Feb 19. Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Pearson et al.

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.

Donnerstag, 10. April 2014

ITP: Acarbose (ACA), 17-α-estradiol (EST), NDGA, Methylene Blue (MB)

Another paper from NIA's Interventions Testing Programme has been published a few months ago. Read it, it's free (1).
This study includes data from their "Cohort 5: [treatment started in] C2009"
 and preliminary data from "Cohort 6: C2010". As is obvious from the starting dates, a mouse lives up to about 1200 days. The authors claim that:
"Here, we report strong evidence for lifespan extension by ACA [acarbose], evidence for a possible effect of EST [17a-estrogen], and strong confirmatory evidence for benefits from NDGA."
Although, then they qualify their statement a little: "Surprisingly, each of these three agents extends lifespan either in males only or (for ACA) much more strongly in males than in females."

Later they also mention a problem that might invalidate a lot of their now-published data:
"One possible reason for the larger or exclusive effects of these compounds on males is the short lifespan of the male controls at two of the three sites (medians of 704, 807, and 924 days from male controls at UT, TJL, and UM, respectively, while female control medians are 864, 918, and 887, Table 1)."

However, a robust intervention must work in both genders. Must. No exceptions made. All validated life extension methods do, e.g. Rapamycin, Calorie Restriction (CR), Methionine Restriction (? maybe?), severe lack of GH (GHRHKO, GHRKO, Ames and Snell dwarfism). If it does not work in females, a mechanism must be shown and follow-up studies should alter the protocol so that it does work.
Remember, interventions solely reducing IGF-1 preferably extend LS in females (the opposite of what we see here). That's one of the reasons why these interventions are not considered established.

Acarbose (ACA) extended maximum lifespan by around 10% in both genders and also led to a similar decrease in weight. Max LS +11% in males, +9% in females. This is consistent with the effect being solely or mostly due to ("crypto-")CR, not glucose absorption kinetics or any other pharmacological effect. The data on median lifespan and weight-adjusted maximum LS is better to the compound:
"...we expected that ACA might produce some survival benefits, although not as much as produced by DR, because the weight reductions from ACA (Fig. 4) were much less than those seen in DR mice. In addition, as weight reductions (% body weight) due to ACA were greater in females [depending on time point, on the order of -20% vs -10%] than in males (Fig. 4), we hypothesized that lifespan effects would, similarly, be larger in females. The results were thus surprising: median lifespan was increased 22% in males and only 5% in females (Fig. 1)."

I maintain that crypto-CR is the most likely explanation until this is refuted by a pair-feeding study. I would not rule out some minor beneficial effect on top of crypto-CR, however.
The authors disagree with me or so it would seem at first glance: "...the lengthened survival for ACA-treated males vs. ACA-treated females cannot be explained by changes in body weight or seen simply as the effect of overall caloric restriction."
But this lengthended lifespan is a meagre 2% difference between +9% and +11%, when it comes to the all-important Maximum LS.

17-α-estradiol (EST) did not extend max LS, although, it had a similar effect to acarbose on weight. Again, this somewhat strengthens the ACA data: not all reductions of bodyweight seem to lead to Crypto-CR.
It is still beyond me why EST was chosen in the first place and for two cohorts, this being the first to publish data! Apparently "it might mimic, in male mice, the beneficial effects produced by estrogen in control females".
This is forgetting that mice as a species do not show a consistent sexual dimorphism in longevity (c.f. ref. 2). Their heterogenous cross (UM-HET3) does, but this could be quite easily an idiosyncratic trait if it doesn't apply to the species as a whole.

NDGA does not look all that promising, but this is only an interim analysis. Its effects seem to be limited to changes in median/avg. lifespan of male mice. However, the effect of NDGA does not extend to females even at the same blood levels as in males. That's a red flag. In the first NDGA study published the authors speculated that they'd have to increase the dose for the female mice so that they have the same blood-levels of the drug:
The blood level was indeed increased in females receiving 5000 ppm to a value similar to that in males receiving 2500 ppm NDGA (Fig. S5), but we saw no evidence for an increase in female lifespan with 70% of the survival curve complete...The high dose reduced female body weight about 14%, 22%, and 23% at 12, 18, and 24 months, respectively, while male weight was only reduced 3–6% (Fig. S6B); thus, the lack of effect of NDGA on female lifespan cannot be explained by concentration in the plasma or by effects on body weight. It is possible that NDGA produces beneficial effects in both sexes but produces harmful effects in females that prevent lifespan extension.
Interestingly, as stated abvoe, NDGA causes considerable weight-loss in females (-1x-2x%) but not males, which could be suggestive of toxicity, at least giving a plausible mechanism for the gender disparity.

Methylene Blue (MB) had a tiny positive effect of 6% on female max LS, but not on male LS. This is very little and could be a statistical fluke. I'd study other substances first before continiung with MB. We're desperate, but not that desperate.
Why was MB chosen in the first place? The rationale presented by the authors is not very convincing. It reads kind of like a supplement ad. We're desperate, I get it. But are we that desperate? Perhaps I'll do a follow-up post with better suggestions for treatments. And I'm not saying MB was a bad shot, just that there should be better substances.

Out of the 4 substances tested none merit any hype, but ACA and NDGA should be followed-up.

Pair-feeding of Acarbose, to match weights between control and intervention group, is the most important follow-up. We should investigate ACA as a CR-mimetic, but not so much on its own merits. We'll see if other interventions targetting glucose metabolism can be successful. Some time ago there were a few successes with AGE-restriction.
I am not sure ACA works as a CR-mimetic in humans as I did not find any documentation of "weight-loss" as a side-effect.

Finish the NDGA study and find out why it does not work in females. The compound remains unvalidated, but interesting. Spindler reported toxicity with high dose NDGA, so let's see how the NIA's highest doses look in the end. It must show maximum lifespan extension in both genders to be interesting from a biogerontologic perspective.

On a side-note, gender-related differences seem to be widespread in mice and their responses to "anti-aging" interventions. I am actually a little surprised, although, I shouldn't be.


1. Aging Cell. 2014 Apr;13(2):273-82. doi: 10.1111/acel.12170. Epub 2013 Nov 19.Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Harrison DE1, Strong R, Allison DB, Ames BN, Astle CM, Atamna H, Fernandez E, Flurkey K, Javors MA, Nadon NL, Nelson JF, Pletcher S,Simpkins JW, Smith D, Wilkinson JE, Miller RA.

2. Handbook of the Biology of Aging, Seventh Edition (Handbooks of Aging). Masoro and Austad.

Dienstag, 25. März 2014

Does reduced GH/IGF signalling extend lifespan? A possible answer.

Berryman et al. (Kopchick lab) recently published a paper (1) that I sort of disagree with. I'd like to take the opportunity to discuss a bigger issue: how can we know the true effects of GH-inihibtion, at least in mouse models? Isn't the data conflicting as Sonntag et al. have shown?

Let's start with a brief introduction to long-lived dwarf mice (1):
"[T]here appears to be a preferential accumulation of excess fat in the subcutaneous depots, which is thought to have metabolically beneficial effects in ... long-lived mice and that may contribute to their counterintuitive association between obesity and life span."
Then the authors say that:
"Not all mouse strains with reduced GH or IGF-1 action show improvements in life span. One example is GH receptor antagonist (GHA) transgenic mice, which were generated in our laboratory more than 20 years ago (22–24)...
The GHA expressed in these mice contains a lysine in place of glycine at position 119 (22–24) in the bGH protein. This single substitution results in the production of a protein that competes with endogenous GH for GHR [Growth Hormone Receptor] binding..."
However, I'd like to contest their claim that these mice fail to show lifespan (LS) extension. I don't think their data is able to show one way or another.

Consider the problem of sample size and power. GHA mice weigh more than classical dwarf mice, e.g. GHR -/- mice, which is due to their incomplete inhibition of GH-signalling. Female GHA mice weigh up to 33% less than controls (ref. 1), males are even heavier. GHR -/- weigh closer to 60-70% less compared to controls! But this also implies that the effects on lifespan will be diminished in GHA mice, albeit non-zero. I think the IGF-1 data also highlights this striking difference:
"In the GHA mice, [serum IGF-1] levels were reduced to about 75–80% the level of controls (P 0.05). In the GHR [KO] mice, levels were reduced to about 20% the level of controls (P 0.0001)." (2)

Lorenzini et al. recently showed that subtle differences in LS due to modest changes in GH/IGF signalling may require n ~ 100 per group (3). In contrast: Coschigano et al."only" used n~50 per group. Normally, a very respectable sample size, but Lorenzinin and Co needed a larger sample size even though their mice have lower IGF1-levels, i.e. ~50% of controls.
In fact, in the study by Coschigano (2), numerically, the median, mean and maximum lifespan is higher in both genders.

Secondly, males show a smaller numerical improvement in lifespan (2):
Although there was a tendency for the GHA mice to live longer than their controls, especially for the females, this difference did not reach statistical significance for either gender.
First of all, this is consistent with other studies also showing a gender disparity. In addition, given their new data (1) it seems that some idiosyncratic side-effect of GH-antagonism or GH/gentoype interaction might be harming male mice.
"...male GHA mice had significantly lower body weights than WT males until 52 weeks, but thereafter, no statistical difference was observed. In contrast, female GHA mice had significantly lower body weights (ranging from 66% to 81% of female littermate controls) throughout the study...40% and 33% of the total body weight of male and female GHA mice, respectively, was attributed to fat by 68 weeks of age compared with 17% for both control males and females of the same age...  
male GHA mice became significantly more obese with advancing age...The mass of all adipose depots was higher in male GHA mice than their littermate controls at 82 weeks of age; however, there was only a significant increase in the mass of subcutaneous and retroperitoneal fat pads (p = 1.0 × 10−6 and p = .04, respectively) "
So either excess fat is harming them, or perhaps, GH antagonism is not maintained throughout the whole lifespan. However, I am not very satisfied with either explanation, since Berryman et al. also showed beneficial changes in male mice, i.e. increased adiponectin and subcutaneous adiposity with low-normal liver triacylglycerol content. There was also a slight uptick in late-life insulin levels and an increase of the leptin-adiponectin ratio which is more consistent with harmful effects.

Third, as much as I hate to say it, but their study (2) is not good enough, not rigorous enough. Their controls on the black 6 background have mean and median lifespans below 800d, while 900d would be expected. Maximum lifespans also appear to be well below the ~1200d expected from a healthy lab mouse.
Overall this weakens conclusions we can draw based on this study, though, it should not introduce much systematic bias. In fact, low LS is often seen as contributing to exaggerated lifespan effects. In particular, with interventions that offset some harmful aspect of questionable husbandry.

Fourth, GH-toxicity might be a real thing biasing low-IGF1 models, which often show compensatory increases in GH levels (5). I do wonder if the GHA-model (Kopchick lab) and the IGF1 hypomorphic mice also show these compensatory increases?
Increased GH-levels have been shown for the liver IGF1 deficient mice (5) and apparently for "Liver-specific GH receptor gene disrupted (LiGHRKO) mice" as well (6), also by Kopchick.

The solution
A meta-analysis  - not a narrative review, not a systematic review - could in principle overcome the issues I raised above, especially sample size and power. Husbandry effects and study quality could be considered as well.

Is the data too heterogenous for analysis? Perhaps, but I don't think so. Meta-analyses of the effects of dietary restriction have been performed, some even comparing different taxa (c.f. 4.a to d).

So far I'd side with the idea that almost all healthy, well-husbanded models of low GH/IGF1 signalling will show delayed aging if there's no frank toxicity. Let's not forgot that toxicity (extrinsic mortality) shouldn't be confused with intrinsic aging - which is what we'd like to study. It's quite possible that things like CVD-toxicity ultimately limit the efficacy of GH/IGF1-signalling reduction.


1. A Dwarf Mouse Model With Decreased GH/IGF-1 Activity That Does Not Experience Life-Span Extension: Potential Impact of Increased Adiposity, Leptin, and Insulin With Advancing Age. Berryman DE, Lubbers ER, Magon V, List EO, Kopchick JJ.J Gerontol A Biol Sci Med Sci. 2014 Feb;69(2):131-41. doi: 10.1093/gerona/glt069. Epub 2013 May 21

2. Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ.
Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology. 2003; 144: 3799–3810.

3. J Gerontol A Biol Sci Med Sci. 2013 Jul 20. [Epub ahead of print]Mice Producing Reduced Levels of Insulin-Like Growth Factor Type 1 Display an Increase in Maximum, but not Mean, Life Span. Lorenzini A, Salmon AB, Lerner C, Torres C, Ikeno Y, Motch S, McCarter R, Sell C.

4.a. Aging Cell. 2013 Jun;12(3):410-4. doi: 10.1111/acel.12061. Epub 2013 Mar 27.Dietary restriction of rodents decreases aging rate without affecting initial mortality rate -- a meta-analysis. Simons MJ1, Koch W, Verhulst S.

4.b. Dietary restriction in rats and mice: a meta-analysis and review of the evidence for genotype-dependent effects on lifespan.Swindell WR.Ageing Res Rev. 2012 Apr;11(2):254-70. doi: 10.1016/j.arr.2011.12.006. Epub 2011 Dec 23. Review.

4.c. Mol Biosyst. 2012 Apr;8(4):1339-49. doi: 10.1039/c2mb05255e. Epub 2012 Feb 10.A meta-analysis of caloric restriction gene expression profiles to infer common signatures and regulatory mechanisms.Plank M1, Wuttke D, van Dam S, Clarke SA, de Magalhães JP.

4.d. Int J Cancer. 2003 Sep 20;106(5):766-70.Energy restriction and the risk of spontaneous mammary tumors in mice: a meta-analysis.Dirx MJ1, Zeegers MP, Dagnelie PC, van den Bogaard T, van den Brandt PA.

5. Reductions in serum IGF-1 during aging impair health span.Gong Z, Kennedy O, Sun H, Wu Y, Williams GA, Klein L, Cardoso L, Matheny RW Jr, Hubbard GB, Ikeno Y, Farrar RP, Schaffler MB, Adamo ML, Muzumdar RH, Yakar S.Aging Cell. 2013 Dec 17. doi: 10.1111/acel.12188. [Epub ahead of print]

6. Endocrinology. 2014 Feb 11:en20132086. [Epub ahead of print]Liver-specific GH receptor gene disrupted (LiGHRKO) mice have decreased endocrine IGF-1, increased local IGF-1 as well as altered body size, body composition and adipokine profiles.List EO1, Berryman DE, Funk K, Jara A, Kelder B, Wang F, Stout MB, Zhi X, Sun L, White TA, Lebrasseur NK, Pirtskhalava T, Tchkonia T, Jensen EA, Zhang W, Masternak MM, Kirkland JL, Miller RA, Bartke A, Kopchick JJ.

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: