Aging as a wound that never begins to heal

Breach of skin integrity is followed by the formation of a blood clot, which is later used as a provisional matrix to gradually replace the missing dermis³. Cells at the very edge of the injury die, and the edge itself undergoes histolysis and debridement, contributing to propagation of damage signals and inflammation, primarily IL-6 and TNF-α⁴. Wounding triggers rapid activation of surrounding stromal cells², mobilization of underlying adipose tissue²² and hair follicles²³, as well as infiltration of immune cells¹⁰. Not only immune, but also stromal cells become pro-inflammatory at the injury site, which at least in a short-term supports the healing process^4,16. An effective repair of skin requires division of tasks with some cells dividing to repopulate the vacant space and others becoming senescent^2,13,16,24. Considering that the elimination of senescent cells has been found beneficial in cases where wounds have not healed for a prolonged period²⁵, it is possible that senescent cells exert different effects on healing during its various phases. Accumulation of LDs has been primarily associated with pro-inflammatory activation of immune cells²⁶, but also stromal skin cells at the injury site¹⁶.

While usually referred to as "regeneration", the process of liver restoration upon injury differs from regenerative processes such as that occurring after a limb amputation of an axolotl. The differences include the lack of directionality of the regrowth; i.e., after an injury, the liver shows a directionless compensatory proliferation of all types of hepatic cells²⁷. In this respect, there is a distinction in the healing pattern, where acute injuries heal by proliferation of liver cells while chronic liver injury can heal by activation of biliary epithelial stem cells²⁸. If liver damage involves the removal of lobes, the following compensatory response will not regrow these lobes but will increase the size of the remaining lobes to restore the original liver-to-body mass ratio²⁷. Yet, it is regeneration in a sense due to the full restoration of the organ's size and function. From the very early stages, liver regeneration is associated with inflammation originating from DAMPs and amplified by cytokines, including IL-6 and TNF-α¹⁹. These attract and activate various types of immune cells that execute histolysis and debridement^10,11, and later participate in its regeneration by growth stimulation, among others¹⁹. Another early response to liver damage, which is associated with regeneration, is an accumulation of LDs (often referred to as TRAS: transient regeneration-associated steatosis)¹⁸. The role of senescence in liver regeneration has not been thoroughly studied, and its impact on different stages of healing remains unknown. However, markers of cellular senescence have been reported in several studies following partial hepatectomy or chemical injury^14,29.

In comparison to the previous examples, brain is arguably the least capable of healing and provides very inaccurate restoration of its original structure upon an injury. Although injury triggers compensatory growth in neuronal progenitors, the newly generated neurons fail to integrate into the existing circuits and frequently do not survive³⁰. In such conditions, glial cells dominate the damage response, leading to glial scar formation³¹. Inflammation is present from the earliest stages of the brain's response to damage, with cytokines including TNF-α and IL-6, amongst others being reseased³². Inflammatory cues and disruption of the blood-brain barrier result in the activation of microglia and the infiltration of various types of immune cells, such as macrophages, neutrophils, B and T cells³³. They participate in the histolysis involving proteases such as MMP9³⁴ and together with microglia execute the subsequent debridement of damaged brain tissue^35,36. Accumulation of LDs has been observed in the zebrafish brain after a needle injury, as well as in post-mortem samples from patients with traumatic brain injury¹⁷. Induction of cellular senescence has been shown in various types of brain injuries, between one day and several months after the insult³⁷, although it is not known whether the impact of senescent cells on healing varies based on the time since injury.

While a detailed description is beyond the scope of this article, similar responses to an injury have been observed for the lungs, heart, skeletal muscle, and kidney^38–41. Although the spatiotemporal properties of these phenotypes in relation to the injury site and healing process are unclear, their presence solidifies the notion of shared injury-related damage responses between organs.

Aging leaves its signature on essentially all levels of molecular composition of cells, including the epigenome, transcriptome, and metabolome, among others⁴². While the direct comparisons of omics profiles between early responses to injuries and aging are infrequent, a recent study utilizing several types of omics investigated whether samples collected from animals and patients under stress conditions and after wounding bear resemblance to aging⁴³. The study has shown that at the levels of epigenetics, transcriptomics, and metabolomics, conditions such as major surgery (and other damaging conditions) show an acceleration of the aging process (albeit in a transient fashion)⁴³, indicating that indeed tissue damage responses bear an overlap with conditions of aging. Similarly, specific epigenetic changes, which closely correlate with aging, known as the epigenetic aging clock, are accelerated in conditions such as infections and various forms of tissue damage^43–45.

On the cellular level, the phenotypes characterizing tissue damage response: inflammation, formation of LDs, infiltration of immune cells and induction of cellular senescence are directly connected to aging. Inflammation affects essentially all aging organs, to the point that it is sometimes considered the main driver of aging⁴⁶. Interestingly, the cytokines most closely connected to aging process are IL-6 and TNF-α⁴⁷, which are also found released upon skin, liver and brain injuries^4,19,32. Cellular senescence, having its own contribution to inflammation¹⁵, is widely considered the embodiment of the aging process (as its name states) with markers of senescence found in essentially all age-related conditions investigated thus far⁴⁸. The same goes for infiltration of immune cells, well documented for aging skin and liver^49,50, but even immune-privileged organs, such as the brain, experience breaching of their parenchyma by immune cells like T cells⁵¹. Finally, accumulation of LDs has been consistently observed to increase in aging organs including the brain⁵² and liver⁵³, among others⁵⁴. While already prominent in the aging process, these injury-like cellular phenotypes are further exacerbated in numerous age-related pathologies. For example, accumulation of LDs⁵⁵, cellular senescence⁵⁶, infiltration of immune cells and inflammation⁵⁷ are exacerbated in Alzheimer's disease and non-alcoholic fatty liver disease⁵⁸.

The morphology of the aging process is usually associated with tissue atrophy⁵⁹, which is seemingly the opposite to the healing-associated tissue growth. However, early stages of response to an injury are actually associated with histolysis and debridement, e.g., in skin³, liver¹⁰, brain^34,35 and in amputated digits⁶⁰, among others⁹. Similar to how the detection of damage can lead to the breakdown and subsequent replacement of structures affected by an acute injury, the detection of damage to structures affected by aging could also lead to their breakdown for a subsequent repair/replacement that in this case never comes. Thus, it is possible that in aging, 'histolysis-like processes' of damage response execute tissue breakdown and contribute to organ atrophy. Moreover, in many cases, aging-related decline in tissue function involves a conversion of functional tissue to fat or fibrotic tissue. Remodeling and degradation of elements of the ECM and/or deposition of fibrotic tissue is one of the most recognizable features of the aging process in organs including skin⁶¹, liver⁵⁸ and brain⁶², while also being at the core of the injury response. While remodeling of the ECM occurring during aging could already provide a potential link to how aged organs behave as if they were injured, another connection is on the side of chronicity of damage perception. Damaged liver restores its mass without scarring, but if the damaging stimulus is persistent, it leads to scarring⁶³. Similarly, prolonged healing of skin as in case of deep wounds exacerbates the amount of deposited collagens⁶⁴. Therefore, it is not only the presence of aging-related damage, but also its persistence that can lead to fibrosis of aged organs. Regarding the conversion of functional tissue to fat or accumulation of LDs in aging organs⁶⁵, it does bear similarity to the observed accumulation of LDs in injuries^16–18. Finally, aging is also associated with a decline in certain support tissues and appendaged, for example a reduction in sub-cutaneous fat⁶⁵ and in a number of hair follicles in skin^66,67. As stem cells of both are known to be utilized during the healing process^22,23, it is possible that the phenotype observed in aging is a reflection of a large-scale (non-local), healing-like response of aged skin. Accordingly, a reduction in stem cells of hair follicles during aging was directly connected to damage response of skin⁶⁸, resembling early stages of an injury²³.

Disseminating the concept from the side of anti-aging interventions, one can deduce that essentially all the core pathways involved in aging have been found necessary for effectively dealing with organ injuries. In other words, if something slows down aging, it likely slows down the healing process as well. Inhibition of mTOR with rapamycin is a known intervention that alleviates aging¹. However, it also leads to delays in wound healing⁶⁹, disrupts proliferation and angiogenesis in models of healing⁷⁰, and suppresses liver regeneration⁷¹. The Erk pathway is one of the main drivers of the injury response and the healing process that is shared between most organs^2,72 and its inhibition was also shown to increase lifespan in a wide range of model organisms^73,74. Similarly, caloric restriction, an intervention consistently proven to extend lifespan¹, slows down the healing process^75,76. Removal of senescent cells extends the time needed for closure of acute wounds^13,16, while also extending lifespan and alleviating age-related diseases⁴⁸. Finally, while I am not aware of evidence that depletion of the immune system slows down aging, an overactive immune system accelerates the aging process⁷⁷ and depletion of immune cells leads to a decline in wound healing and regeneration rates^4,19, suggesting a functional connection.

Cancer is one of the most common age-related pathologies, with a risk of occurring in essentially all cellular tissue structures. Referred to as the "wound that never heals"^87,88, cancer often occurs at the site of an injury or as a consequence of the healing process^89,90. The common features of healing and cancer include elevated proliferation, migration, and angiogenesis, and the detailed characteristics of this overlap have been recently reviewed⁹¹. Our research results further support this concept, showing that the spatial range of healing can be visualized as a lump of tissue mass surrounding the wound, which promotes proliferation and angiogenesis, among others, resembling the characteristics of a tumor².

It is necessary to stress that the aging process is the main risk factor for cancer across tissues⁹². At the same time, cancer exhibits features that are often opposite to aging, which is burdened with tissue atrophy and loss of cells. Thus, going back to the phases of the healing process, the behavior of cancer matches the proliferation phase, while aging corresponds better to the inflammatory phase. One question this hypothesis leads to is whether aging-induced cancer is another façade of the "injury-like" appearance of aged organs. The immediate next question is whether cancer results from an attempt to progress with the healing process, moving from the inflammatory to proliferation phases. As anti-aging treatments (reducing "injury-like" properties) reduce cancer risk^93,94, it is intriguing to speculate that dampening the damage response in aged organs may prevent the transition from the inflammatory to the proliferative phase. At the same time, abolishing the induction of injury-associated responses such as immune cell infiltration or cellular senescence could lead to cancer. Consistently, mice deprived of a functional immune system or the machinery responsible for senescence induction show an increased risk of cancer development⁹¹. In summary, the "wound that never stops healing" phenotype of cancer could represent a dysregulated process of dealing with damage responses induced in aged organs, thus attempts to transition aged organs from an inflammatory to a proliferative phase could potentially lead to cancer.

Regeneration is a relatively poorly understood process of accurately reconstituting damaged tissues. While regeneration shares at least some of the tissue damage responses, such as inflammation, infiltration of immune cells, and cellular senescence²⁴, it differs in how these responses transition to reconstitute the damaged region. Arguably, the component that distinguishes regeneration from healing is the ability to re-specialize existing cells towards replacing the missing ones. This can be done either directly, through re-specialization of existing cells (followed by compensatory growth), as in morphallaxis of hydra, or indirectly, through de-specialization of cells into pluripotent cells and formation of so-called 'blastema,' as in epimorphic regeneration of an axolotl⁷. While the inter-species differences seem insurmountable, such processes are possible in mammals⁸ and can be induced artificially to a limited extent^95,96. For the latter, one approach is to introduce secretory factors such as members of the FGF and BMP family, which change the trajectories of damage responses from healing to regeneration^95,96. Another approach is to force de-specialization of cells using methods such as reprogramming⁹⁷. While to my knowledge, the former has not been tested against aging, the latter has shown some promise against aging-associated conditions⁹⁸. Hypothetically, the induction of regeneration should remove the damage that underlies the inflammatory phase of healing and, consequently, the phenotypes of the damage responses thus delaying or even preventing aging process (Fig. 2). This hypothesis is consistent with organisms having a profound capacity to regenerate, showing negligible aging⁹⁹. In summary, the hypothesis presented here defines aging as a progressive form of tissue injury and proposes a set of interventions aimed at alleviating aging (by suppressing damage responses) or treating aging (by resolving these responses and regenerating tissues).