Mapping p16 and p21 Markers of Cellular Senescence in Humans by Tissue and Age

In that part of the research community focused on the role of cellular senescence in aging, the consensus is that the markers presently used to identify senescent cells are placeholders waiting for a better approach. They are not sufficiently universal. Senescent cells might be different enough in different tissues to require tissue specific approaches to assess their presence to a usefully exact degree.

This point is illustrated by the results of a recent survey of p16 and p21 in humans by tissue type and age. That neither p16 nor p21 expressing cells increased in number with age in lung tissue strongly suggests that senescent cells in lungs are meaningfully different from those elsewhere in the body, at least in this aspect of their biochemistry. Humans should certainly be expected to have an increase in senescent cells in the lungs, as in all tissues, with advancing age. The same argument applies to the apparent absence of p16 and p21 expressing cells in muscle.

Why do we want reasonably accurate measures of senescent cell burdens by tissue? Because this will be needed as a part of the development and validation of senolytic therapies capable of selectively destroying senescent cells. Early programs are getting by with the existing markers, but as the myriad age-related diseases that can be turned back via senolytic treatments are explored in greater depth, better assays will be needed. In clinical practice, people will want an assessment of senescence burden, not just symptoms, as a way to decide when to apply treatments prior to the development of significant dysfunction. These are important considerations, and the present markers are just not up to the task.

Survey of senescent cell markers with age in human tissues

Cellular senescence, triggered by sublethal damage, is characterized by indefinite growth arrest, altered gene expression patterns, and a senescence-associated secretory phenotype. While the accumulation of senescent cells during aging decreases tissue function and promotes many age-related diseases, at present there is no universal marker to detect senescent cells in tissues.

Cyclin-dependent kinase inhibitors 2A (p16/CDKN2A) and 1A (p21/CDKN1A) can identify senescent cells, but few studies have examined the numbers of cells expressing these markers in different organs as a function of age. Here, we investigated systematically p16- and p21-positive cells in tissue arrays designed to include normal organs from persons across a broad spectrum of ages.

Increased numbers of p21-positive and p16-positive cells with donor age were found in skin (epidermis), pancreas, and kidney, while p16-expressing cells increased in brain cortex, liver, spleen, and intestine (colon), and p21-expressing cells increased in skin (dermis). The numbers of cells expressing p16 or p21 in lung did not change with age, and muscle did not appear to have p21- or p16-positive cells. In summary, different organs display different levels of the senescent proteins p16 and p21 as a function of age across the human life span.

Comments

If better genetic markers become available, you've got to wonder what the effects of combining Oisin's lipid nanoparticles and suicide gene technology with them would be? Greater life extension in mice?

Posted by: Jimofoz at March 19th, 2020 5:37 PM

Hopefully yes. We are quite blindfolded when experimenting with senescent cells so anything that improve the d├ętection and understanding will help. We don't even know exactly how they harm. For example, apoptotic cells are any inflammatory, so inducing apoptosis in ScC might have double action of removing Sasp and secreting antiinlammatory factors.

Posted by: Cuberat at March 19th, 2020 8:53 PM

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