Survey of senescent cell markers with age in human tissues

M Laura Idda,Martina Rossi,Rachel Munk,Kotb Abdelmohsen,Waverly G Mcclusky,Valeria Lodde,Myriam Gorospe

doi:10.18632/aging.102903

Abstract

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.

Highlights

Senescence is a cellular response to sublethal harm and developmental signals characterized by generally irreversible growth arrest, alterations in metabolic state, and changes in morphology and gene expression programs [1, 2]
In order to catalog the abundance of cells expressing the senescence markers p16 and p21 in distinct age groups and tissues, we custom-designed tissue arrays (FFPE) comprising a panel of normal healthy tissues obtained from human donors of different ages (Array II, BioChain Institute; FDA 35, Pantomics, Inc.)
Graphs represent the quantification (%) of p16-positive (A) and p21-positive (B, D) cells from 5 tissue cores from independent donors per organ and age group; data represent the means ±SD from 5 different donors. p values were determined by one-way ANOVA with Tukey adjustments for multiple comparisons where appropriate. **, p < 0.01; *, p < 0.05

Summary

Introduction

Senescence is a cellular response to sublethal harm and developmental signals characterized by generally irreversible growth arrest, alterations in metabolic state, and changes in morphology and gene expression programs [1, 2]. Senescent cells express and secrete factors that promote inflammation (e.g., the interleukins IL6, IL1B, and IL8), degrade the extracellular matrix (matrix metalloproteases, MMPs), and promote angiogenesis (e.g., vascular endothelial growth factor, VEGF); this trait is known as the senescence-associated secretory phenotype (SASP) [3, 4]. In addition to these features, senescent cells express a β-galactosidase (SA-β-gal) enzyme active at pH 6 that reflects a robust lysosomal activity [5, 6]. In addition to telomere shortening resulting from replicative exhaustion, various damaging stresses may lead to senescence, such as direct DNA damage from irradiation and chemicals, and mitochondrial dysfunction with increased production of reactive oxygen species (ROS) (reviewed in [1])

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Conclusion