A study published in Aging shows that not only do different cell types express different levels of the senescence markers p16 and p21, these markers increase, and occasionally decrease, at different rates.
Senescence and its markers
Senescent cells are known to be harmful in excess, as they do not support their tissues and excrete the senescence-associated secretory phenotype (SASP), which causes age-related systemic inflammation (inflammaging). Cellular senescence is a hallmark of aging, and many researchers seek to remove senescent cells through drugs known as senolytics. The researchers of this study list diseases such as sarcopenia, obesity, and diabetes as reasons to control senescent cell count.
To that end, they have surveyed a panoply of cells from multiple organs for two senescence markers, p16 and p21, with five donors per cell type, and the results were greatly different between cell types. Muscle cells, for example, did not show any p16 nor p21 expression at all. The tissue of the epidermis, the outer layer of the skin, showed the conventional results, with p16 expression minimal at young and middle ages but spiking at old age; p21 rose somewht more smoothly through middle age. The dermis, the lower layer of the skin, showed different results; dermal tissue does not express p16 but does increasingly express p21 with age. Both markers were shown to rise smoothly with kidney tissue.
However, other cell types showed less conventional results. For example, p21 in lung tissue was shown to be generally higher than in other tissues, even in youth, and does not increase with age. The endocrine and exocrine regions of the pancreas behaved differently, and middle-aged endocrine pancreatic tissue was shown to have higher p21 expression than older tissue. Liver tissue varied greatly between donors, but for both p16 and p21, a trough at middle age was observed.
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.
This study leaves three unanswered questions. The first question, which the researchers invoke, involves other markers of cellular senescence, such as SA-β-Gal and factors associated with the SASP. The researchers were unable to study these markers, which would paint a more complete picture.
The second question involves the field of senolytics. As senescence markers do not always rise linearly with age, particularly in tissues that have high levels of these markers even in youth, it raises the possibility that senolytics that target these markers may cause unwanted side effects and suggests a need for tissue-specific senolytic approaches.
The third question is why the levels of these markers are the way they are, most notably when the markers do not strictly increase with age. More research and analysis is needed to confirm that these interesting results are truly representative of living tissue and explain the function of these proteins within each individual cell type.