No Great Surprises in a Recent Study of Skin Aging

A recent study of skin aging brings no great surprises. The authors are focused on epigenetic changes that alter the rate of production of various proteins, and thus also alter the behavior and function of cells and tissues. People with younger-looking skin at a given chronological age also tend to have younger-looking patterns of gene expression, the process of generating proteins from their DNA blueprints. Aging is a global phenomenon, and progression of all of its aspects tend to correlate to some degree in any given individual. Among the more easily identified differences in the epigenetics of skin aging are those related to well-known processes of aging, such as cellular senescence.

The contributions to aging can be separated into primary (or intrinsic) and secondary (or extrinsic) sources, though the dividing line is far from clear-cut. Primary aging happens regardless of choice, side-effects of the normal operation of cellular metabolism that result in the accumulation of waste and molecular damage. Secondary aging is avoidable: the consequences of line items such as excess fat tissue, smoking, and in the case of skin excessive exposure to sunlight, or photoaging. Both primary and secondary aging operate through overlapping mechanisms. That is well illustrated here, in that the researchers find more markers of cellular senescence in skin that is more frequently exposed to sunlight. One can hypothesize about radiation damage to cell structures in this context, but the point is that secondary aging can and does work through the usual mechanisms more commonly associated with primary aging, such as those listed in the SENS rejuvenation research programs. The root causes inside the body are the same, but how those causes are triggered, and to what degree, can depend on circumstances.

The sort of research noted here does seems a little tautological at times, in that younger-looking people are younger-looking because they are physiologically younger. Younger gene expression is just another facet of being younger - it isn't a root cause, and isn't even a particularly satisfying explanation in many cases. All of the items measured in the study are downstream consequences of the actual internal root causes of aging, such as senescent cell accumulation or cross-linking in the extracellular matrix, and those root causes grow at a somewhat different pace in every individual. Some of that is happenstance, but the majority of it is due to lifestyle choices, at least until quite late in life when genetic resistance to high levels of damage becomes influential. Get fat, age more rapidly. Be sedentary, age more rapidly. Take up smoking, and age more rapidly. In the context of skin, sit around in the sun too much and age more rapidly.

Aging increases mortality rate, and exactly when death arrives is a roll of the dice. Some people die early, some people live for a few decades longer. These are small differences considered in the grand scheme of things, however. We should not care all that much about natural variations in human longevity that arise due to lifestyle and chance in the present environment. These differences are small in comparison to what might be achieved in the decades ahead through the implementation of rejuvenation therapies that repair and reverse the root causes of aging - so it is there that our attention should be focused.

Expression of Certain Genes May Be Key to More Youthful Looking Skin

Some individuals' skin appears more youthful than their chronologic age. New research indicates that increased expression of certain genes may be the key to intrinsically younger looking - and younger behaving - skin. "It's not just the genes you are born with, but which ones turn on and off over time. We found a wide range of processes in the skin affected by aging, and we discovered specific gene expression patterns in women who appear younger than their chronologic age."

To produce a comprehensive model of aging skin, researchers collected and integrated data at the molecular, cellular, and tissue levels from the sun-exposed skin (face and forearm) and sun-protected skin (buttocks) of 158 white women ages 20 to 74 years. As part of the study, the team looked for gene expression patterns common in women who appeared years younger than their chronologic age. The physical appearance of facial skin was captured through digital images and analysis. Skin samples were processed for analysis and saliva samples were collected for genotyping. The analyses revealed progressive changes from the 20s to the 70s in pathways related to oxidative stress, energy metabolism, cellular senescence, and skin barrier. These changes were accelerated in the 60s and 70s. Comparing sun-exposed and sun-protected skin samples revealed that certain genetic changes are likely due to photoaging.

The gene expression patterns from the women in the study who were younger appearing were similar to those in women who were actually younger in age. These women had increased activity in genes associated with basic biologic processes, including DNA repair, cell replication, response to oxidative stress, and protein metabolism. Women with exceptionally youthful-appearing facial skin in older age groups also had higher expression of genes associated with mitochondrial structure and metabolism, overall epidermal structure, and barrier function in their facial epidermal samples, as well as dermal matrix production.

Age-induced and photoinduced changes in gene expression profiles in facial skin of Caucasian females across 6 decades of age

Gene expression and ontology analysis of photoexposed and photoprotected skin samples in Caucasian women across 6 decades revealed progressive, age-related changes from their 20s to their 70s. All these aging processes accelerated in the 60s and 70s, co-occurring with menopause. Histologic elastosis was apparent in photoexposed sites (face and dorsal forearm) beginning in the 40-year-old cohort, suggesting that earlier molecular processes are important precursors to what later becomes histologically and clinically apparent changes in skin appearance. The results demonstrate that younger-looking skin in older cohort groups shows gene expression patterns that mimic chronologically younger skin on a molecular level. This finding offers the potential for future inquiry into biologic factors that slow evolution of aging processes.

Genes related to DNA repair and replication, cell growth and survival, chromatin remodeling, response to oxidative stress, autophagy, and protein metabolism are expressed differently in youthful skin than in older-appearing skin. In addition, epidermal structure and barrier, as well as dermal matrix, are also better maintained in youthful-appearing skin, with increased expression of genes such as CDH1, DSC3, and LAMA5 likely contributing. CDH1 and DSC3 are components of cell-cell junctions in the epidermis, and LAMA5 is essential for attachment of keratinocytes to the basement membrane. Expression of these three genes was significantly increased in youthful-appearing skin, intermediate in average-appearing skin, and decreased in older-appearing skin.

In addition, dermal genes associated primarily with extracellular matrix structure were differentially expressed depending on appearance of the facial skin. Genes associated with cellular metabolism also decreased more markedly with age in the epidermis of older- than younger- or average-appearing facial skin. This pattern mirrored individual genes representing examples of different processes related to mitochondrial structure and metabolism. A decrease in cellular energy metabolism has previously been linked to visible signs of skin aging such as wrinkling.

Cell senescence, indicated by CDKN2A expression, increased markedly in the photoexposed arm and facial skin, particularly in the epidermis. CDKN2A codes for multiple proteins including p16INK4a, which is associated with suppression of cell replication and induction of cellular senescence - key causes of aging. Even small fractions of senescent cells can contribute to visible aging and underlying processes, including inflammation in photoexposed skin sites. Increased CDKN2A expression corresponded with sun exposure and aged appearance of facial skin.

In summary, genetics play a fundamental role in setting the pathways of aging, but how aging occurs is associated with changes in expression of these genes over time. Genes associated with youthful-appearing skin represent fundamental cellular repair and metabolic processes, as well as functional properties such as skin barrier. Furthermore, the observed differences in onset and time progression of changes in gene expression across key aging pathways might present interesting biomarkers and targets to provide further insights into skin aging.


And it's no great surprise that you do another post diminishing other peoples hard work, in anticipation that SENS / ADG will ride in with the holy grail to save humanity

This blog has become stale

Posted by: xxx at November 30th, 2017 5:20 AM

These results are not proof, but they are a hint that senescent cells may make skin look older, and removing them may make skin look younger. I think this is important, because as soon as there is a treatment that makes people look younger, public interest in regenerative biotechnology may increase. I think much the same result would be had on public opinion if a cure for baldness came along.

Posted by: Jim at November 30th, 2017 6:08 AM

I think it's more than a hint. If extra DNA damage is leading to extra skin aging, and the women less exposed to sun developed the same symptoms, only later, then it is a near certainly that senescent cells are a major contributor to that (hard to say of course if the accumulation is caused by greater production or reduced clearance).

Didn't the mice experiments with senolytics show hair regrowth?

Posted by: Mark at November 30th, 2017 8:48 AM

@Mark - Mice regrow hair at the drop of a hat unfortunately. Largely hairless humans are a different proposition.

Posted by: Jim at November 30th, 2017 10:02 AM

And also mice have very proliferative-able cells, more so than humans. It may be that the removal of senescent cells will mobilise better replacements however, even in older humans. We'll have to wait for human trials for confirmation of this however!

Posted by: Mark at November 30th, 2017 11:56 AM

Both AGEs in the skin and Wrinkles in the skin accumulate in a linear manner throughout one's life. Towards the end of life senescent cells accumulate in an exponential manner. It is not like there has ever been a case of someone that had good smooth skin at 85, but their skin quality deteriorated rapidly from 85 to 90. However there are numerous anecdotes of people that are active and spry at 85, but then gravely infirm by 90. Thus I conclude skin wrinkling is more caused by AGEs and other cross links, than by senescent cells. I am more inclined to think that cross links accelerate senescent cell accumulation than the converse, but they may be independent problems.

Posted by: JohnD at November 30th, 2017 9:17 PM

I agree with xxx that it is not necessary to try diminish the value of a good work just because it does not fit SENSE / ADG narrative. I also agree with others that offering visible results of even minimal rejuvenation of aging skin would do more good for aging research than the endless begging for money, a position taken by SENS folks.

Posted by: yyy at December 3rd, 2017 10:17 AM
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