Regenerative of tissue is a very complex affair in which all sorts of different cell types and systems participate in their own individual ways, collaborating in an intricate dance that results in reconstruction. The overall theme is the same in all tissues, but the details vary widely by tissue type. So in skin, for example, eccrine sweat glands, the primary type of sweat gland, serve as the anchor points from which new epithelium grows. The sweat glands are reservoirs of highly regenerative cells that spring into action when needed, and construct new structures outwards from the gland, meeting in the middle between glands. The research I'll point out today shows that these cell populations retain regenerative capacity even in older age, but the authors argue that age-related changes in the physical characteristics of skin act to sabotage regenerative efforts, making it harder to build cohesive cellular structures.
Physical characteristics derive from the extracellular matrix, a lattice of support constructed by the cells that occupy its spaces. The details of extracellular matrix molecular structure determine the properties of tissue for everything from skin to bone: flexibility, elasticity, stiffness, resilience, ability to bear load, and so forth. Anything that disrupts this structure and its maintenance will alter its properties, usually for the worse. One important form of age-related damage is cross-linking, in which forms of sugary metabolic byproducts bind with molecules of the extracellular matrix, linking and limiting them. Some types of cross-link are long-lived, and our biochemistry is unable to remove them. This is one of the processes responsible for loss of elasticity in skin and blood vessels. Then there are senescent cells that accumulate in tissues with age, producing inflammation and acting to remodel the surrounding extracellular matrix in uncoordinated, detrimental ways. Other aspects of aging also have their contributions to make to the declining quality of the extracellular matrix, some more direct, some less so.
What can be done about this? Periodically repair the damage. Design drugs that can break down the cross-links that our biochemistry cannot handle. Develop drugs and gene therapies that selectively kill senescent cells. Follow through to create the full SENS portfolio of envisaged rejuvenation treatments, each of which repairs one of the forms of damage that cause aging, including those that drive the aging of skin. Given a functional rejuvenation toolkit, all of our sweat glands could get back to working as they did in youth, provided with an extracellular matrix freed from the burden of molecular damage. All too little effort is directed to this goal, even in this day and age of revolutionary progress in biotechnology, and that is one of the great shames of our era.
A group of scientists and dermatologists are now looking at the role sweat glands play in how aging skin recovers from wounds. It's a step to better learn about aging skin, in order to better treat - and slow - the process. Their research compared 18 elderly subjects' skin to 18 young adults' skin, to see how each group healed from skin lesions. The lesions were smaller than the diameter of a pencil eraser, performed under local anesthesia. The researchers had already determined eccrine sweat glands, which are located throughout the body, are important for wound closure. They are major contributors of new cells that replace the cells that were lost due to injury.
"Since we know elderly people tend to sweat less than young adults, we concentrated on this healing function of sweat glands." In young people, they discovered sweat glands contributed more cells to wound closure than in aged adults. The cells in aged skin weren't as cohesive, either. Fewer cells participating, spaced further apart, means a delay in wound closure and a thinner repaired epidermis in aged versus young skin. It wasn't that the sweat glands were less active in older people, rather, that the environment in the aging skin had been slowly degraded, making the skin structures less able to support the new cells that were generated. "Limiting skin damage during the aging process is likely to limit the negative impact of aging on wound repair. This study teaches us that poor wound healing and wrinkling and sagging that occur in aging skin share similar mechanisms."
Human skin heals more slowly in aged vs. young adults, but the mechanism for this delay is unclear. In humans, eccrine sweat glands (ESGs) and hair follicles underlying wounds generate cohesive keratinocyte outgrowths that expand to form the new epidermis. Our results confirm that the outgrowth of cells from ESGs is a major feature of repair in young skin. Strikingly, in aged skin, although ESG density is unaltered, less than 50% of the ESGs generate epithelial outgrowths during repair (vs. 100% in young). Surprisingly, aging does not alter the wound-induced proliferation response in hair follicles or ESGs. Instead, there is an overall reduced cohesiveness of keratinocytes in aged skin. Reduced cell-cell cohesiveness was most obvious in ESG-derived outgrowths that, when present, were surrounded by unconnected cells in the scab overlaying aged wounds.
Failure to form cohesive ESG outgrowths may reflect impaired interactions of keratinocytes with the damaged extracellular matrix (ECM) in aged skin. Previous work from our group and others has characterized in detail the age-associated damage to the skin dermal ECM, which includes increased collagen fiber fragmentation, reduced ECM resistance, and decreased tissue mechanical force. Although the ECM is well known for its role in providing structural scaffolds for embedded cells, recent studies have highlighted the importance of the ECM as underlying substrate for collective cell migration. For instance, increasing ECM rigidity (Young's modulus) enhances cellular traction forces and cell-cell adhesion. Thus, it is likely that reduced rigidity of skin ECM, as it occurs with aging, would reduce cell-cell cohesiveness as we observed in vivo. Altogether, these observations suggest that damage to the ECM in aged skin may mediate reduced cell-cell cohesiveness and thereby reduce the efficiency of the re-epithelialization process in aged skin.