Cellular Models of Aging and Senescence

Abstract

Aging, a state of progressive decline in physiological function, is an important risk factor for chronic diseases, ranging from cancer and musculoskeletal frailty to cardiovascular and neurodegenerative diseases. Understanding its cellular basis is critical for developing interventions to extend human health span. This review highlights the crucial role of in vitro models, discussing foundational discoveries like the Hayflick limit and the senescence-associated secretory phenotype (SASP), the utility of immortalized cell lines, and transformative human induced pluripotent stem cells (iPSCs) for aging and disease modeling and rejuvenation studies. We also examine methods to induce senescence and discuss the distinction between chronological time and biological clock, with examples of applying cells from progeroid syndromes and mitochondrial diseases to recapitulate some signaling mechanisms in aging. Although no in vitro model can perfectly recapitulate organismal aging, well-chosen models are invaluable for addressing specific mechanistic questions. We focus on experimental strategies to manipulate cellular aging: from "steering" cells toward resilience to "reversing" age-related phenotypes via senolytics, partial epigenetic reprogramming, and targeted modulation of proteostasis and mitochondrial health. This review ultimately underscores the value of in vitro systems for discovery and therapeutic testing while acknowledging the challenge of translating insights from cell studies into effective, organism-wide strategies to promote healthy aging.

Keywords: cardiovascular aging; cellular aging; epigenetic reprogramming; in vitro models; induced pluripotent stem cells (iPSCs); mitochondrial dysfunction; neurodegeneration; progeroid syndromes; senescence; senolytics.

Figure 1

Timeline of major findings from in vitro cellular models in aging. This figure illustrates the evolution of cellular aging research from the 1960s to 2025, highlighting key discoveries and interventions derived from in vitro cellular models. The timeline is divided into five eras: foundation era (1960s), telomere biology era and mechanistic understanding (1980s–2000s), reprogramming revolution (2006–2010s), precision manipulation era (2010–2020s), and precision manipulation era (2015–2020s to 2025).

Figure 2

Two cellular models for aging research: (A) Primary Cells offer high physiological fidelity, but limited experimental control. They are derived directly from donors and possess inherent heterogeneity, biographical complexity (biological variation from different sources), and accumulation of epigenetic and metabolic memory. Manipulation of these cells is more constrained. Defining specific states of cells is limited to the selective elimination of specific subpopulations, such as senescent cells. “Steering” approaches using tools like Yamanaka factors or senolytics achieve partial and limited rejuvenation. This model is particularly valuable for studying authentic age-related pathology where cellular damage accumulation is essential and validating therapies in naturally aged cells. (B) Induced pluripotent stem cells (iPSCs) provide total experimental control, but at the cost of authenticity. The reprogramming process involves resetting cells to the embryonic state, a complete molecular reset that erases all hallmarks of aging. However, subsequent differentiation yields functionally immature cells (e.g., fetal neurons) that do not fully capture the adult pathophysiological function. To study aging, these cells can be subjected to artificial stressors to create an “artificially aged” phenotype. Although this does not fully recapitulate the multifaced aspect of cellular aging, it is valuable to understand the molecular signaling mechanisms.