Defined p16^High Senescent Cell Types Are Indispensable for Mouse Healthspan

Area of Science:

• Cellular senescence
• Aging research
• Molecular biology

Background:

• Cellular senescence, marked by p16Ink4a, contributes to age-related diseases.
• Removing senescent cells is a proposed strategy to extend lifespan.
• The specific roles and consequences of senescent cell removal in vivo are not fully understood.

Purpose of the Study:

• To investigate the dynamics of p16Ink4a-positive senescent cells during aging.
• To determine the functional consequences of eliminating p16Ink4a-positive senescent cells.
• To explore therapeutic strategies for age-related decline.

Main Methods:

• Generation of two knockin mouse models for p16Ink4a.
• Genetic lineage tracing to track senescent cell accumulation.
• Acute and continuous elimination of p16Ink4a-positive senescent cells.

Main Results:

• Age-induced p16Ink4a senescence is a gradual process starting around 10-12 months.
• The majority of senescent cells were liver sinusoidal endothelial cells (LSECs), followed by macrophages and adipocytes.
• Elimination of senescent cells led to disrupted blood-tissue barriers, fibrosis, and deteriorated health.
• Senescent LSECs are not replaced and play vital structural and functional roles.

Conclusions:

• Senescent LSECs are critical for maintaining tissue integrity and function in aging organisms.
• The removal of senescent cells, particularly LSECs, has detrimental health consequences.
• Delaying senescence or finding ways to replace senescent LSECs may be effective strategies to slow aging.