Rescuing Senescent Cells by Delivering New Mitochondria Sounds Like a Risky Proposition

Mitochondria are effectively power plants, hundreds of these organelles per cell working to create the chemical energy store molecule adenosine triphosphate. Mitochondria are the descendants of ancient symbiotic bacteria, and retain many bacterial characteristics, including a small genome, the mitochondrial DNA, and the ability to replicate. Mitochondrial dysfunction is one of the paths by which cells can become senescent, entering a state of growth arrest while secreting an inflammatory set of signals, but mitochondria are in any case involved in the transition to senescence in response to other forms of damage or dysfunction. In youth, senescent cells are quickly destroyed by their own programmed cell death processes or by the immune system. In older people, these cells accumulate, contributing to tissue dysfunction and the chronic inflammation of age.

In today's open access paper, the authors propose treating skin aging by delivering whole mitochondria into senescent cells, thereby rescuing their function. In recent years, various approaches to introducing mitochondria into target cells have been demonstrated. It also appears to be the case that cells naturally transfer, eject, and ingest mitochondria under a range of circumstances. Is rescuing the usual forms of senescent cells found in old tissues a good idea, however? If cellular senescence is largely due to mitochondrial dysfunction, which it may be under some circumstances, then the proposal here isn't completely unreasonable. But cells become senescent for a variety of good reasons, including nuclear DNA damage that is potentially cancerous, and which can occur in skin as the result of exposure to UV radiation. Selectively destroying senescent cells in skin sounds like a safer approach than attempting to rehabilitate them.

For what it is worth, delivering functional and undamaged mitochondria appears best targeted to normal cells in the aging body, to boost their function in an environment of damaged and dysfunctional mitochondria. Indeed, that has been attempted. Mitochondrial function does decline with age in tissues throughout the body. Perhaps something should be done about that. While it is unclear as to whether newly introduced mitochondria would remain functional for long in the aged environment, the strategy sounds worth a try, given the evidence to date for it to enhance tissue function in the short term.

Bases for Treating Skin Aging With Artificial Mitochondrial Transfer/Transplant (AMT/T)

The perception of mitochondria as only the powerhouse of the cell has dramatically changed in the last decade. It is now accepted that in addition to being essential intracellularly, mitochondria can promote cellular repair when transferred from healthy to damaged cells. The artificial mitochondria transfer/transplant (AMT/T) group of techniques emulate this naturally occurring process and have been used to develop therapies to treat a range of diseases including cardiac and neurodegenerative. Mitochondria accumulate damage with time, resulting in cellular senescence. Skin cells and its mitochondria are profoundly affected by ultraviolet radiation and other factors that induce premature and accelerated aging. In this article, we propose the basis to use AMT/T to treat skin aging by transferring healthy mitochondria to senescent cells, possibly revitalizing them.

Mutations related to monogenic mitochondrial disorders can cause fragmentation of the mitochondrial network in the cell. Affecting this network hampers its capacity to maintain mitochondrial DNA (mtDNA) stability. When good and damaged mitochondria are unable to fuse within networks, they can't exchange healthy mtDNA or get rid of damaged DNA copies. This ultimately leads to dysfunctions in the cell and premature senescence. For instance, patients with fibromyalgia suffer from oxidative stress and inflammation of the skin which has been linked to mitochondrial dysfunction. Healthy skin depends on the maintenance of functional mitochondria, which could be a target for the development of medical and cosmetic anti-aging treatments.

To our knowledge, there is no effective treatment available to the public to reverse skin aging by targeting mitochondria. The few existing therapeutic options focused on the mitochondria are under development and still, need further in vitro assays and clinical validation. In addition, no available products, including topical application of natural substances and antioxidants, offer a substantial recovery from many skin aging symptoms such as mtDNA instability, respiration, collagen production, neovascularization, and localized inflammation.

In this hypothesis article we present the idea and arguments of using the artificial mitochondria transfer/transplant (AMT/T) technique as a possible skin anti-aging therapeutic. It has been observed previously that the use of AMT/T in vitro, in vivo, and clinically promotes cell and tissue recovery in different diseases, with effects that could be used to repair skin damage. For example, MitoCeption, one of many AMT/T techniques, induces cell proliferation, migration, and increased respiratory ATP production, processes needed to repair the damage in aged skin. PAMM MitoCeption (Primary Allogeneic Mitochondria Mix Transfer by MitoCeption) repaired UV radiation damaged cells by recovering the loss of metabolic activity, mitochondrial mass, mtDNA sequence stability in addition to decreasing p53 expression. Beyond in vitro applications, AMT/T showed to have regenerative effects in vivo, in diseases such as heart and brain ischemia. AMT/T applied clinically to pediatric patients with myocardial dysfunction has also shown positive results on ischemic injured tissues.

Our hypothesis regarding AMT/T as an antiaging skin therapeutic could be tested in vitro, in vivo, and clinically, to promote the applications of this technique. The possibility to transfer new mitochondria to senescent or age-induced harmed cells in the skin could represent a plausible option to treat the effects of aging.

Comments

Indeed mito transplants sound a bit unnecessary, provided we can have nice senoblation and seeding with skin stem cells. The neurons, on the other hand, live for very long and need thousands of mitochondria. If they can get renewed mitochondria it might be a big change.
It remains to be seen if the treatment is possible and what would be the clinical outcome.

It is just about of time we get lucky and one of the treatments actually works and is easy to commercialize...

Posted by: cuberat at September 24th, 2020 7:50 PM

On the subject of skin aging, I recently read an interview with DeGrey that was bullish on Revel's prospects for bringing effective glucosepane breakers to market. He kinda made it sound as though the key breakthrough has already made and all that remains are pesky clinical trials. Is this true?

If it is, what kind of results do we anticipate? Is it really the case that a treatment for wrinkles might be just a few years away??? Surely that would bring an enormous amount of money into the field, and would do most of our marketing for us? More than RMR, my gut tells me a treatment for skin aging that really works, and does so with sufficiently impressive results, is the thing that would do most to shatter our age old narratives about aging and reveal the potential of the field to the wider world. Every person who undertook such a treatment would become a walking billboard for aging's mutability.

Posted by: Benjamin S Esler at September 25th, 2020 12:20 AM

@Benjamin: AFAIK, they have several candidate compounds and are testing them in mice.

Posted by: Antonio at September 25th, 2020 1:53 AM

I think another booster for looks would be something against sarcopenia since facial ageing is caused by a deterioration of skin as much as loss of muscle (and bone). Iron out a saggy face and you have a smooth saggy face.

Posted by: Barbara T. at September 25th, 2020 12:14 PM

Rejuvenation of skin, muscle and bone, even if it works as advertised, will not extend human life span, because most aged humans die of senescent heart, lungs, kidneys and other internal organs. This kind of treatment would not be considered true rejuvenation.

The purpose of fighting aging should be longer life and also feeling , looking and functioning younger than one's chronological age ( for example: 80 year old looking and feeling like 20 year old).

Posted by: Nicholas D. at September 25th, 2020 7:45 PM

"The purpose of fighting aging should be longer life and also feeling , looking and functioning younger than one's chronological age."

I agree 100%, but the appearance of skin and muscle is readily apparent whereas proving extra longevity requires a long wait. So the point that I and I think others were making was that in order to convince people to channel funding towards anti-aging research, visible results will help.

Basically, we need quick evidence-based marketing to speed up the process...

Posted by: Barbara T. at September 25th, 2020 8:53 PM

Yes, Barbara that's exactly what I mean. People need to see results, and ideally they need to have no choice but to see them. They need to see them when they walk down the street, upon the faces of their friends and in images of newly wrinkle free celebrities on their televisions. Results in mice may impress the scientific community, which is still obviously very useful, but if we're talking about enlisting the general public, they need to be shaken out of their complacency (and even confronted) by unavoidable and obvious success. I can't think of anything that would so disentangle the concepts of biological and chronological age as making older people actually look young again, even if the job is still far from complete.

Posted by: Ben at September 25th, 2020 9:42 PM

I don't know if this will someday make skin look young again, but for now it seems to restore healing function:

A newly identified genetic factor allows adult skin to repair itself like the skin of a newborn. The discovery has implications for wound treatment and preventing some of the aging process in skin. Researchers identified a factor in the skin of baby mice controlling hair follicle formation. When it was activated in adult mice, their skin was able to heal wounds without scarring. The reformed skin even included fur and could make goose bumps.

Lef1 expression in fibroblasts maintains developmental potential in adult skin to regenerate wounds

https://elifesciences.org/articles/60066

"Here, we identify regenerative factors in neonatal murine skin that transforms adult skin to regenerate instead of only repairing wounds with a scar, without perturbing development and homeostasis."

Posted by: Jones at September 30th, 2020 2:51 PM

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.