5 replies to this topic

[reason]

Cellular senescence is a response to damage or environmental factors such as toxins, wounds, and oxidative stress. It removes cells from the processes of growth and replication, and probably serves, at least initially, as a way to reduce cancer risk. In this paper, researchers remove mitochondria from senescent cells and see measures of their state improve as a result. The publicity materials head in the wrong direction, I think, by talking about aging versus cellular senescence - these are two very different things, and the aging of individual cells has no direct relationship to aging of the organism.

Growth in the number of senescent cells lingering in tissues is a contributing cause of degenerative aging due to their overall bad behavior, but so is mitochondrial damage. This research could be taken as evidence for one way which mitochondrial damage and dysfunction is important in the mechanisms of aging, but it can also be taken as a straightforward improvement in the understanding of how cells manage their transition into senescence. In either case, we already know that both of these processes are targets for near future rejuvenation therapies.

A team of scientists has for the first time shown that mitochondria, the batteries of the cells, are essential for ageing. The researchers found that when mitochondria were eliminated from ageing, senescent cells they became much more similar to younger cells. This experiment was able for the first time to conclusively prove that mitochondria are major triggers of cell ageing. This brings scientists a step closer to developing therapies to counteract cellular senescence, by targeting mitochondria.

As we grow old, cells in our bodies accumulate different types of damage and have increased inflammation, factors which are thought to contribute to the ageing process. The team carried out a series of genetic experiments involving human cells grown in the laboratory and succeeded in eliminating the majority, if not all, the mitochondria from ageing cells. Cells can normally eliminate mitochondria which are faulty by a process called mitophagy. The scientists were able to "trick" the cells into inducing this process in a grand scale, until all the mitochondria within the cells were physically removed. To their surprise, they observed that the senescent cells, after losing their mitochondria, showed characteristics similar to younger cells, that is they became rejuvenated. The levels of inflammatory molecules, oxygen free radicals and expression of genes which are among the markers of cellular ageing dropped to the level that would be expected in younger cells.

The team also deciphered a new mechanism by which mitochondria contribute to ageing. They identified that as cells grow old, mitochondrial biogenesis, the complex process by which mitochondria replicate themselves, is a major driver of cellular ageing. "This is the first time that a study demonstrates that mitochondria are necessary for cellular ageing. Now we are a step closer to devising therapies which target mitochondria to counteract the ageing of cells."

Link: http://www.eurekaler...u-mst020316.php

View the full article at FightAging

[Turnbuckle]

They identified that as cells grow old, mitochondrial biogenesis, the complex process by which mitochondria replicate themselves, is a major driver of cellular ageing.

 

 

 

So presumably if mitochondria have become dysfunctional, then creating duplicates of these dysfunctional mitochondria will be a bad thing for the cell. But biogenesis per se should not be a bad thing. That said, why have these mitochondria gone bad? MtDNA mutations are one problem, and epigenetic changes are another. C60 may be able to reverse epigenetic changes--at least hypothetically--while exercise can reverse the mutation burden, at least in mutator mice--

 

Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice.

 

 

BACKGROUND:

Human genetic disorders and transgenic mouse models have shown that mitochondrial DNA (mtDNA) mutations and telomere dysfunction instigate the aging process. Epidemiologically, exercise is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of exercise are well established, the molecular mechanisms instigating these observations remain unclear.

 

RESULTS:

Endurance exercise reduces mtDNA mutation burden, alleviates multisystem pathology, and increases lifespan of the mutator mice, with proofreading deficient mitochondrial polymerase gamma (POLG1). We report evidence for a POLG1-independent mtDNA repair pathway mediated by exercise, a surprising notion as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here, we show that the tumor suppressor protein p53 translocates to mitochondria and facilitates mtDNA mutation repair and mitochondrial biogenesis in response to endurance exercise. Indeed, in mutator mice with muscle-specific deletion of p53, exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, or mitigate premature mortality.

 

CONCLUSIONS:

Our data establish a new role for p53 in exercise-mediated maintenance of the mtDNA genome and present mitochondrially targeted p53 as a novel therapeutic modality for diseases of mitochondrial etiology.

 

http://www.ncbi.nlm....pubmed/26834962

 

 

 

P53 requires a Goldilocks level of zinc-- 

 

The missing zinc: p53 misfolding and cancer.

 

The p53 tumor suppressor is a transcription factor that contains a single zinc ion near its DNA binding interface. Zn(2+) is required for site-specific DNA binding and proper transcriptional activation. In addition to its functional significance, zinc plays a dominant role in determining whether p53 folds productively or misfolds. Insufficient zinc and excess zinc cause p53 to misfold by distinct mechanisms which both result in functional loss. The zinc-binding status of p53 in the cell is impacted significantly by the presence of tumorigenic mutations and by metal ion homeostasis. This review discusses mechanisms by which zinc modulates folding and misfolding of p53, how improper metal binding and release leads to loss of function and cancer, and how misfolding can be rescued by metallochaperones.

 

http://www.ncbi.nlm....pubmed/21072344

 

 

 

And as for metallochaperones--

 

Synthetic metallochaperone ZMC1 rescues mutant p53 conformation by transporting zinc into cells as an ionophore.

Edited by Turnbuckle, 04 February 2016 - 09:24 PM.

[maxwatt]

They killed all the mitochondria in aged cells..   If you did thatin your muscles, for instance, they would get weaker and weaker. 

You only want to selectively kill the bad oes.

Apoptosis of the bad mitochondria and neogenesis of the good ones.  I believe that is what resveratrol, other things, do, but just not enough.

[corb]

They killed all the mitochondria in aged cells..   If you did thatin your muscles, for instance, they would get weaker and weaker. 

You only want to selectively kill the bad oes.

Apoptosis of the bad mitochondria and neogenesis of the good ones.  I believe that is what resveratrol, other things, do, but just not enough.

 

I suspect the cells managed to get working mitochondria after all their original ones were destroyed otherwise they wouldn't have been able to survive.

 

 

Tunneling nanotubes (TNTs) are F-actin-based membrane tubes that form between cells in culture and in tissues. They mediate intercellular communication ranging from electrical signalling to the transfer of organelles. Here, we studied the role of TNTs in the interaction between apoptotic and healthy cells. We found that pheochromocytoma (PC) 12 cells treated with ultraviolet light (UV) were rescued when cocultured with untreated PC12 cells. UV-treated cells formed a different type of TNT with untreated PC12 cells, which was characterized by continuous microtubule localized inside these TNTs. The dynamic behaviour of mCherry-tagged end-binding protein 3 and the accumulation of detyrosinated tubulin in these TNTs indicate that they are regulated structures. In addition, these TNTs show different biophysical properties, for example, increased diameter allowing dye entry, prolonged lifetime and decreased membrane fluidity. Further studies demonstrated that microtubule-containing TNTs were formed by stressed cells, which had lost cytochrome c but did not enter into the execution phase of apoptosis characterized by caspase-3 activation. Moreover, mitochondria colocalized with microtubules in TNTs and transited along these structures from healthy to stressed cells. Importantly, impaired formation of TNTs and untreated cells carrying defective mitochondria were unable to rescue UV-treated cells in the coculture. We conclude that TNT-mediated transfer of functional mitochondria reverse stressed cells in the early stages of apoptosis. This provides new insights into the survival mechanisms of damaged cells in a multicellular context.

 

http://www.nature.co...dd2014211a.html

[Mind]

As mentioned by others, this is an interesting result, but not directly applicable with current biotechnology or given our current understanding of cell metabolism. Taking all of the mitos out of a cell would render it almost useless. I wonder if the cells in this study went into a form of stasis, without a normal source of energy, and thus seemed to not age. Or did the cells really become "younger" (by known metrics)?

[Turnbuckle]

As mentioned by others, this is an interesting result, but not directly applicable with current biotechnology or given our current understanding of cell metabolism. Taking all of the mitos out of a cell would render it almost useless. I wonder if the cells in this study went into a form of stasis, without a normal source of energy, and thus seemed to not age. Or did the cells really become "younger" (by known metrics)?

 

 

I think it is excellent evidence for the mitochondrial theory of aging.