Cells become senescent constantly throughout life, in response to damage, stress, injury, or simply reaching the Hayflick limit on replication. In youth the immune system promptly removes this cells, but with age this clearance becomes inefficient, allowing senescent cells to accumulate. When senescent, a cell ceases to replicate and devotes its energies to the secretion of a mix of pro-growth, pro-inflammatory signals, the senescence-associated secretory phenotype (SASP). This is useful in the short term context of coordinating recovery from injury or drawing the immune system to destroy potentially cancerous cells, but becomes harmful when sustained. It is disruptive to tissue structure and function, a contribution to the chronic inflammation of aging.
Worse, and as noted in today's open access paper, the SASP provokes a greater incidence of senescence in distant cells. The more senescent cells in any one location, the more likely it is that cells elsewhere in the body will become senescent in response to stresses. Cellular senescence may be one of the more important mechanisms linking the age-related decline of function in any one organ with the age-related decline in function of other organs. The authors of this paper focus on the liver, but the point could just as well be made of the kidney, or visceral fat deposits, or other internal organs.
Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ
The SASP is a central mediator of the non-autonomous effects of senescent cells. Here, we demonstrate that senescence can be transmitted to and affect the function of distant organs in a systemic manner. In the context of acute injury, senescence has often been described as part of a finely tuned mechanism with overall beneficial effects for wound healing. SASP factors have been shown to induce reprogramming in neighbouring cells, facilitating tissue regeneration. However, following severe injury, this mechanism may have the opposite effect, systemically, through excessive SASP production, including senescence itself. In turn, this excessive stimulus for senescence can be associated with compromised organ function.
Systemic transmission of senescence may be relevant to several diseases. Here, we use a series of models of hepatocyte-specific senescence to model an acute senescence phenotype, such as the one observed during acute liver failure. Acute liver failure is, itself, characterized by sequential multi-organ failure, typically beginning with the kidney progressing to also involve the brain, lungs, and other organs. This clinical progression may, at least in part, be underpinned by the systemic transmission of senescence. The data in patients with acute indeterminate hepatitis, showing that increased hepatocellular expression of p21 at initial presentation before multi-organ failure can predict ensuing multi-organ failure, requirement for liver transplant and/or death, provide evidence for a biomarker that both allows early risk stratification and selection of patients for specific therapies.
Similarly, the observation that TGFβ signalling is a central driver of systemic transmission of senescence may pave the way for therapeutic approaches in diseases where this phenomenon occurs. Whilst this effect may either be independent of solely p21-dependent senescence or a phenomenon related to TGFβ activity outside of senescence, it is in line with the beneficial effects of senolytics and senomorphics that have been elegantly demonstrated on numerous pathologies. Further research is required to dissect out the direct causal link between senescence in the primary tissue and the systemic effects and how they are affected by factors such as disease site or specific senescence phenotype, chronicity of senescence, and the interaction with concurrent or pre-existing senescence in other organs. Our results demonstrate that systemic transmission of senescence can induce systemic organ dysfunction, which may be central to multi-systemic sequelae in many diseases.
View the full article at FightAging
