Senescent cells at the crossroads of aging, disease, and tissue homeostasis

Abstract

Originally identified as an outcome of continuous culture of primary cells, cellular senescence has moved beyond the culture dish and is now a bona fide driver of aging and disease in animal models, and growing links to human disease. This cellular stress response consists of a stable proliferative arrest coupled to multiple phenotypic changes. Perhaps the most important of these is the senescence-associated secretory phenotype, or senescence-associated secretory phenotype -a complex and variable collection of secreted molecules release by senescent cells with a number of potent biological activities. Senescent cells appear in multiple age-associated conditions in humans and mice, and interventions that eliminate these cells can prevent or even reverse multiple diseases in mouse models. Here, we review salient aspects of senescent cells in the context of human disease and homeostasis. Senescent cells increase in abundance during several diseases that associated with premature aging. Conversely, senescent cells have a key role in beneficial processes such as development and wound healing, and thus can help maintain tissue homeostasis. Finally, we speculate on mechanisms by which deleterious aspects of senescent cells might be targeted while retaining homeostatic aspects in order to improve age-related outcomes.

Keywords: cellular senescence; disease drivers of aging; homeostasis; progeria; senolytics.

FIGURE 1

Pathological consequence of senescence. Senescent cells promote degeneration conditions in multiple organ systems. In the eye they can promote macular edema, retinopathy, and cataracts. In the brain senescent cells can drive neurodegeneration and outcomes that resemble Parkinson's or Alzheimer's disease. In the lung and liver, senescent cells can promote fibrosis. Both cardiac and endothelial senescent cells can promote cardiovascular disease. Senescent pancreatic beta cells drive diabetes, and in the musculoskeletal system senescent cells drive both sarcopenia and osteoarthritis. These represent a subset of conditions shown to be targetable by senotherapeutic strategies in animal models.

FIGURE 2

Disease drivers of senescence. Multiple chronic diseases and their treatments result in both aging and cellular senescence. Genotoxic progerias, photodamage, and cancer treatments such as radiation and chemotherapy drive senescence through strand breaks and other forms of DNA damage. Nucleotide reverse transcriptase inhibitors (NRTIs) used in HIV therapy can deplete or cause mutations in mitochondrial DNA. Finally, progeroid laminopathies such as Hutchinson‐Guilford Progeria Syndrome (HGPS) and protease inhibitors (PIs) used for HIV therapy can drive nuclear lamina disruption. Each of these in turn can drive senescence and potentially promote age‐related pathologies.

FIGURE 3

Homeostatic mechanisms of senescence. Senescent cells are required for multiple homeostatic processes. They appear at sites of cutaneous wounds to promote healing, and can reside in lung tissue until required to help regeneration. During development senescent cells appear in the embryo to drive pattern formation and promote placentation. Finally in the chorionic membrane, senescent cells can send signals the promote parturition.