Repeated Cycles of Incomplete Healing as a Cause of Aging

The authors of the open access paper here have an intriguing view of the way in which regenerative processes run awry with age, and thus contribute to the aging process. As is the case for many single mechanism proposals regarding aging, I think that the viewpoint is useful, but the mechanism in question is probably not as important to aging as proposed here - it is one of many issues. Nonetheless, this is an interesting example of the way in which it is hard to pin down the ordering of specific mechanisms in aging; it is quite possible to argue for A to cause B or B to cause A and present a good case for either. Here, for example, dysregulated regeneration is thought to be a cause of senescent cell accumulation, whereas it is equally possible to argue that the chronic inflammatory signaling produced by senescent cells disrupts the usual short-lived cycle of inflammation that is necessary to coordinate various cell populations necessary to the regenerative process.

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.



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