Incomplete Healing as a Cause of Aging: The Role of Mitochondria and the Cell Danger Response (2019) Naviaux

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Biology (Basel). 2019 May 11;8(2). pii: E27. doi: 10.3390/biology8020027.

Incomplete Healing as a Cause of Aging: The Role of Mitochondria and the Cell Danger Response.
Naviaux RK.

Abstract
The rate of biological aging varies cyclically and episodically in response to changing environmental conditions and the developmentally-controlled biological systems that sense and respond to those changes. Mitochondria and metabolism are fundamental regulators, and the cell is the fundamental unit of aging. However, aging occurs at all anatomical levels. At levels above the cell, aging in different tissues is qualitatively, quantitatively, and chronologically distinct. For example, the heart can age faster and differently than the kidney and vice versa. Two multicellular features of aging that are universal are: (1) a decrease in physiologic reserve capacity, and (2) a decline in the functional communication between cells and organ systems, leading to death. Decreases in reserve capacity and communication impose kinetic limits on the rate of healing after new injuries, resulting in dyssynchronous and incomplete healing. Exercise mitigates against these losses, but recovery times continue to increase with age. Reinjury before complete healing results in the stacking of incomplete cycles of healing. Developmentally delayed and arrested cells accumulate in the three stages of the cell danger response (CDR1, 2, and 3) that make up the healing cycle. Cells stuck in the CDR create physical and metabolic separation-buffer zones of reduced communication-between previously adjoining, synergistic, and metabolically interdependent cells. Mis-repairs and senescent cells accumulate, and repeated iterations of incomplete cycles of healing lead to progressively dysfunctional cellular mosaics in aging tissues. Metabolic cross-talk between mitochondria and the nucleus, and between neighboring and distant cells via signaling molecules called metabokines regulates the completeness of healing. Purinergic signaling and sphingolipids play key roles in this process. When viewed against the backdrop of the molecular features of the healing cycle, the incomplete healing model provides a new framework for understanding the hallmarks of aging and generates a number of testable hypotheses for new treatments.

KEYWORDS:
cell danger response; crabtree effect; de-emergence; healing cycle; integrated cell stress response; metabokines; mitochondria; pasteur effect; purinergic signaling; sphingolipids
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https://www.ncbi.nlm.nih.gov/pubmed/31083530
https://www.mdpi.com/2079-7737/8/2/27/htm

This research is not explicitly about ME/CFS but I decided to put it here anyway because it's about CDR and because of the acknowledgements in the full paper:

Acknowledgments
RKN thanks the many families with primary mitochondrial disease, autism spectrum disorder (ASD), and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) who have helped make this research possible. RKN thanks Scott McAvoy from the UCSD Digital Media Lab for preparing the art work for the healing spiral in Figure 2, and Vamsi Mootha, Sarah Calvo, and Jonathan Monk for the bioinformatic analysis of mitochondrial proteins and enzymes.
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ScottTriGuy said:
Hhmmm - I kind of thought most people with ME look younger then their age, which would be the opposite of the hypothesis.
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I look considerably younger than my age but I've always assumed that that was because of lack of UV exposure, because I have been mostly housebound for decades. In terms of stuff going wrong with bits of me, I seem to be right on target, age-wise!
 
Mij said:
I look like a mature Bond girl.
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Me too

Well actually I look like a wizened old fart ..so I think when it comes to looking younger than your age I am clearly the exception

In fact I seem to remember in my 20’s and 30’s everyone always used to mistake me for 5-10 years younger and I used to smile and reveal my age to their surprise.

Now though ..it’s the opposite ...grey and balding (including eyebrows..don’t know what happened to the ends) which is severely limiting my Bond girl work ..it’s all but dried up...now i would be lucky to get an incontinence pants advert ...sigh
 
Postdoctoral Fellowship
A postdoctoral fellowship is available in the Naviaux Lab at the University of California, San Diego School of Medicine. The successful applicant will join an active mass spec lab to study the metabolomic and exposomic features of a number of chronic complex disorders. Current projects include autism, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Lyme disease, chronic pain syndromes like fibromyalgia, autonomic disorders like POTS, autoimmune disorders like PANS, and PANDAS, and several others.

The lab is fundamentally interested in the mechanisms of chronic illness, the healing cycle, and the role of chemical changes in our food chain, water, and air as contributors to this growing problem. If there is an interest, additional studies may involve the systematic screening of natural products from rainforest and ocean ecosystems for novel drug candidates. This position will receive bioinformatic support from a group of talented computational biologists and digital graphic artists who are developing new methods to visualize the metabolic networks that define health and disease. The duration of the fellowship is typically 2-4 years.
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https://jobs.sciencecareers.org/job/499330/postdoctoral-fellowship/
 
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