Another Proposed Link Between Short Telomeres and Dysfunctional Mitochondria
This research has been doing the rounds:
This week researchers from the Dana-Farber Cancer Institute reported that the length of telomeres - which shorten with age - determines virtually every aspect of aging from wrinkles and gray hair to the onset of dementia, diabetes, and heart disease. At least that was the case in the mice they studied in a report published in Nature."We think we've identified the core pathway that really helps explain many different theories of aging," says study co-author Dr. Ronald DePinho, a geneticist at Dana-Farber. "Our study provides a unified field theory for aging."
In a nutshell, once telomeres shorten to a particular length, aging accelerates. Shortened telomeres allow the cell's DNA to become damaged, which activates a gene, p53. This sets off a warning to shut down the cells' normal growth and division cycle until the damage can be fixed or, if not, the cells die. At the same time, cells with short telomeres have power plants, or mitochondria, that are no longer operating at full capacity. This leads to malfunction in crucial organs like the brain, heart, liver, and pancreas, as well as a loss of muscle, and eventually extreme weakness and frailty.
(The paper is at Nature if you're the sort who likes to read primary sources). That's an ambitious declaration from the researcher quoted above - I can only imagine it's taken somewhat out of context and then hyped up by the science writer for the introductory paragraph, as it is certainly the case that damaged mitochondria and shortening telomeres are only two of the possible reasons we suffer age-related degeneration. Many of the other causes of aging involve a build up of varying forms of damaging waste product that the body cannot remove - mechanisms which are quite capable of causing disability and death on their own, telomere shortening or no telomere shortening.
That said, telomeres, mitochondria, and p53 are all large and healthy areas of research when it comes to the biology of aging. I imagine that anyone would be pleased to produce good evidence that might mechanically tie them all together, such that one or more are secondary effects rather than primary causes. From an economic perspective, we should all be hoping that some of our present candidates for the primary causes of aging turn out to be secondary effects - because then we don't have to devote any time towards developing repair biotechnologies to fix them.
On a closer reading of the new research, I have to say that it looks to me very much like an independent confirmation of discoveries from 2007 and 2008 relating to mitochondrial damage, telomere length, and the enzyme telomerase. In a nutshell, it may be that telomere shortening is entirely driven by mitochondrial dysfunction:
Researchers have put forward evidence to suggest that telomere shortening is caused by accumulated damage to mitochondrial DNA - essentially collapsing two areas of intense interest for gerontologists down to one root cause, if confirmed. ... [It may be the case that] poorly functioning mitochondria lead to telomere shortening, and telomerase somehow improves mitochondrial function to prevent that shortening. This is in place of the more expected path of undoing ongoing telomere shortening by adding extra repeat sequences to the end of the telomeres - that being the better understood function of telomerase.
I don't immediately see anything in the Nature paper that would rule out this interpretation of the link between these two fundamental mechanisms of aging. Like the earlier researchers, this present group also found that boosting telomerase activity improved mitochondrial function, though I believe they are arguing that the improved function happens as a secondary result of interactions between telomere length and p53. There's certainly plenty of room amidst the uncertainty for contradictory interpretations at this stage.
The link between mitochondrial free radical release and telomere length was elucidated in papers in 2010 especially the Passos paper. Ultimately to suggest that mitochondrial "rule" telomere function discounts the effects of epigentics lifestyle and other non mitochndrial based inputs. It IS clear the mitochondria are involved in M1(senstatic activation) and M2 (apoptosis)events especially apoptosis via accelerated release of free radicals. But this is primarily a membrane mediated effect via p53. And double stranded DNA breaks AND telomere shortening are the triggers required for this, not alterations or damage to mitochondrial DNA at least at first. This does not suggest a central role for the mitochondrial DNA in this "type of aging" although I have no doubt mitochondrial damage whether via its DNA or dysfunction of its membrane permeability or inadequate electron transport modalities are potential causes or contributors to aging. The genes coded for in mitochondrial DNA suggest more of an externally controlled role than a defining central one. I would focus more on membrane control of the mitochondria related to free radical damage, omega 3 fatty acid deficits and the like to explain the ultimate role of the mitochondria in aging. Remember that many of the constituents of the electron transport chain are coded for via non mitochondrial DNA and many of these constituents are synthesized from "out to in" on the mitochondrial membrane
If we take your comments literally you are correct, there is nothing in the paper you cited that disproves a governing role of mitochondria in aging but i am willing to state that the mitochondrial theory of aging is fundamentally wrong. Time will tell whose "belief system" is correct. Best Dr Dave author The Immortality Edge (wiley 2010)
I actually think that mitochondrial dysfunction (by whatever cause) is the root cause and telemere shortening is the effect. Not the other way around. One reason why I think this is because different tissues in the body have different replication rates. For this to be the case and for other reasons as well, telemere shortening (and elongation) appears to be a regulated process. What causes the regulatory mechanism itself to fail is the cause of aging. I suspect that this regulatory mechanism is somehow based on mitochondrial function.
It would be very easy to get into a "who's right and wrong" debate here but that is pointless since in truth no one knows the final answer yet. But if you are interested in this topic and want to make scientifically based comments please read the Passos paper and remember the title of the paper in Nature cited above:
Telomere dysfunction induces metabolic and mitochondrial compromise... not vice versa. In every case I know of to date WBC (rapid replication) telomere length correlates very well with the biologic age of the organism and of tissue specific disease such as heart brain joint etc. While the absolute number does not correlate because of inherent differences in telomere length (myocardium has long telomeres) the pattern of degradation and length is correlative. Telomere shortening is regulated: by the number of cell divisions needed to attempt to maintain functioning tissues as well as the degree of telomerase activation (see Rejuvination Research and TA-65) oxidation, methylation, glycosylation acetylation,exercise diet etc etc. None of these systems are independent of mitochondrial function but a double stranded DNA break can occur with no mitochondrial dysfunction and yield the same results by the same pathway. Classic mitochondrial disease affect 500,000 Americans. Aging affects everyone on the planet. In the end run we all benefit from the research no matter which belief system it favors.
Another problem with the telemere shortening theory of aging is that it cannot account for why tissues composed of cells that divide less frequently also show the same level of aging as those that divide more frequently.
Kurt it would appear from your response that you did not read my comment and/or that you have a “belief system” based on the mitochondrial theory of aging. The difference between beliefs and reality is often research and there is a lot of it suggesting that mitochondrial function is primarily controlled by telomeres.
Your comment about telomere theory not explaining all cells aging smacks of someone’s blog post somewhere. Here are some things to consider
Slowly replicating cells often have “shorter telomeres” and even lower nascent telomerase activity than rapidly replicating ones. WBC/bone marrow lines have very active telomerase relative to other somatic cells although it is not “high” by any means. The normal distribution of telomere length is actually quiet wide as is the actual expression of telomerase in different cell lines at replication, but the general utility of WBC telomere length is applicable to other tissues as well especially in light of ‘aging and disease” That is short WBC telomeres often correlate with short telomeres in other diseased tissues albeit the absolute lengths are different. Cancer chemo for example often nails WBC etc because both cell lines are rapidly diving and telomerase dependent.
There are other mechanisms telomeres/telomerase may explain aging in less active cell as Dr DePinho reports below. Once you actually entire articles instead of blog comments or abstracts alone it gets harder to justify the mitochondrial theory of aging.
Here is a small excerpt from DePinho that sums it up:
“…the mechanistic basis for comparably severe compromise of less proliferative tissues has been an enigma. Here, combined transcriptomic, molecular, genetic and functional analyses on cellular and organismal levels established a direct molecular link between telomere dysfunction and repression of PGC-dependent processes of PGC-dependent processes of mitochondrial biogenesis/function, gluconeogenesis and oxidative defense…”
While a half dozen or so studies are not enough to prove one theory of aging over another and no one knows where the final answer will be the telomere will be at the center of it. If you can show me one recent study that shows the mitochondria control the fate of telomeres and not vice versa as several recent studies have shown I will listen.
One other thing regarding the "mitochondrial theory of aging" the phenotype of mitochondrial disease is not aging, its muscle weakness. The phenotype of Werners and Hutchison-gilford Progerias both examples of genetic telomere dysfucntion IS aging.