Subcellular structure, heterogeneity, and plasticity of senescent cells

Abstract

Cellular senescence is a state of permanent growth arrest. It can be triggered by telomere shortening (replicative senescence) or prematurely induced by stresses such as DNA damage, oncogene overactivation, loss of tumor suppressor genes, oxidative stress, tissue factors, and others. Advances in techniques and experimental designs have provided new evidence about the biology of senescent cells (SnCs) and their importance in human health and disease. This review aims to describe the main aspects of SnCs phenotype focusing on alterations in subcellular compartments like plasma membrane, cytoskeleton, organelles, and nuclei. We also discuss the heterogeneity, dynamics, and plasticity of SnCs' phenotype, including the SASP, and pro-survival mechanisms. We advance on the multiple layers of phenotypic heterogeneity of SnCs, such as the heterogeneity between inducers, tissues and within a population of SnCs, discussing the relevance of these aspects to human health and disease. We also raise the main challenges as well alternatives to overcome them. Ultimately, we present open questions and perspectives in understanding the phenotype of SnCs from the perspective of basic and applied questions.

Keywords: SASP; cellular senescence; dynamics; heterogeneity; subcellular structure.

FIGURE 1

Overview of senescence inducers, molecular mechanisms, and cellular alterations. (a) Main senescence inducers, including replicative and induced (premature) senescence. (b) Top and center—cytosolic and nuclear pathways leading to cell cycle arrest. On the left, a box is shown with the genes and proteins that primarily carry out senescence. On the bottom are shown pathways driving in the progression from quiescence to senescence. The key features of SnCs are shown on the right, indicating specific sections of the manuscript where each is discussed.

FIGURE 2

Subcellular alterations of SnCs. In the center is shown a representative model of a SnC with subcellular alterations. The boxes surrounding the cell represent details of the main subcellular changes comparing SnCs to non‐SnCs. Each box summarizes the main structural and functional changes observed in these components in SnCs. A detailed description of the subcellular changes, including the senescence inducer, cell model, and other findings, can be found in Tables [Link], [Link]. PE, phosphatidylethanolamine; PS, phosphatidylserine; SAHF, senescent‐associated heterochromatin foci; NPC, nuclear pore complex; MOM, mitochondrial outer membrane; MT, microtubules; IF, intermediate filaments; AF, Actin filaments or microfilaments; EVs, extracellular vesicles; CCF, chromatin; Ac, acetylation; ER, endoplasmic reticulum; UPR, unfolded protein response.

FIGURE 3

Open questions in cellular senescence. (a) Phenotypic plasticity of SnCs, including molecular states (S1–S3) and morphologies (a–c). (b) Heterogeneity and plasticity of SCAPs. Left—schematic western blot representing the increase in the expression of pro‐survival proteins in SnCs. Open question 1: Do transitions between different states or phenotypes lead to changes in SCAPs? Open question 2: Do SCAPs vary over time in single SnCs? (c) Dynamics of SASP over time. #1, #2, and #3 represent SASP molecules. (d) Heterogeneity and plasticity of SASP. Left—schematic dot plot representing the increase in SASP in a senescence‐enriched population. (e) Representative model of dimensionality reduction to identify SnCs' subpopulations along the progression of the phenotype. RS, replicative senescence. (f) In each condition from i to vi, intra‐populational heterogeneities are shown: Colors represent different patterns of gene expression, while different cell shapes represent morphometric heterogeneity.