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

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.

Figure 1

The metabolic features of the health and healing cycles. Abbreviations: CDR—cell danger response, eATP—extracellular ATP, CP1-3—checkpoints 1, 2, and 3, DAMP—damage-associated molecular pattern, DARM—damage-associated reactive metabolites, SIGLEC—sialic acid binding immunoglobulin-type lectin, e.g., CD33-related SIGLECs (CD33r-SIGLECs), Sia-SAMP—sialoglycan self-associated molecular pattern.

Figure 2

Repeated cycles of incomplete healing lead to aging and age-related disease. The spiral represents sequential turns of the healing cycle throughout life. Colored cells in the boxes on the right represent cells that have been delayed or arrested in a stage of the healing cycle. The decreased size of some boxes represents the loss in tissue volume from cell loss and atrophy. In this example, most arrested or delayed cells in the merge on the right after 60 and 90 years are in CDR2 (green). This will create an increased risk of proliferative disorders such as diabetes, heart disease, and cancer. Color code: CDR1 cells—red; CDR2 cells—green; CDR3 cells—yellow. Abbreviations: A—wakeful activity and nutrient intake. M1—mitochondria adapted for cell defense, reactive oxygen, nitrogen, and aldehyde production; M0—mitochondria adapted for cell growth and Warburg metabolism; M2—mitochondria adapted for oxidative phosphorylation (oxphos).

Figure 3

The hallmarks of aging as natural products of incomplete healing and the cell danger response [3,39]. Black font: hallmarks that oppose aging. Red font: hallmarks that promote aging. Abbreviations: CDR—cell danger response, ICSR—integrated cell stress response, DDR—DNA damage response, BMR—basal metabolic rate, T°—basal body temperature, HIF1α—hypoxia inducible factor 1α, PARP—poly ADP ribose polymerase, NAD+—nicotinamide adenine dinucleotide, ADPR—adenosine diphosphate ribose, SAM—S-adenosyl methionine, AcCoA—acetyl CoA, α-KG—alpha ketoglutarate, SAH—S-adenosyl homocysteine, PPi—pyrophosphate, NUDIX—nucleoside diphosphate X hydrolases, e.g., NUDT5, ECM—extracellular matrix.