Bcl-xL in Cellular Senescence and Human Longevity

An accumulation of lingering senescent cells takes place with advancing age. Senescent cells are created throughout life, entering the senescent state in response to reaching the Hayflick limit on replication, or DNA damage, or signaling from other senescent cells, or to a toxic environment. Senescent cells cease replication and instead generate a potent mix of inflammatory and pro-growth signals, the senescence-associated secretory phenotype (SASP). In youth near all senescent cells are rapidly destroyed, either by programmed cell death, or by the immune system. With advancing age, however, the processes of clearance slows down and the pace of creation picks up. The outcome is an increasing number of senescent cells in tissues throughout the body.

Senescent cells perform useful tasks in the short term. They help to coordinate regeneration following injury, and draw the attention of the immune system to damaged cells with a raised risk of becoming cancerous. When they linger for the long-term, however, their signaling produces chronic inflammation, changed behavior in neighboring cells, and disruption of tissue structure and function. In this way, senescent cells directly contribute to the onset and progression of numerous age-related conditions.

Targeted destruction of senescent cells via senolytic treatments has been shown to produce rejuvenation and extended life span in mice. Some of the earliest senolytic drugs target Bcl-xL, a protein that acts to hold back the onset of apoptosis and consequent cell death. Unlike normal cells, senescent cells are primed to enter apoptosis, and require significant activity of anti-apoptosis mechanisms in order to survive. Sabotaging these mechanisms thus selectively destroys senescent cells.

As noted in today's open access paper, Bcl-xL is upregulated in very long-lived humans in comparison to their shorter-lived peers. This Bcl-xL activity may assist in slowing aging modestly, raising the odds of surviving to an advanced age, via maintenance of a more functional immune system. That more functional immune system, more capable of destroying senescent cells, may counteract the downside of senescent cells being more able to resist apoptosis and self-destruction given higher Bcl-xL expression.

Bcl-xL as a Modulator of Senescence and Aging

Centenarians, the most aged individuals, should accumulate senescent cells and suffer from their deleterious effects, however, they enjoy a compression of morbidity. We have shown that they overexpress B-cell lymphoma-extra large (Bcl-xL). Bcl-xL could avoid an excessive burden of senescent cells through the regulation of intrinsic apoptosis, mitochondrial bioenergetics and oxidative stress. On the other hand, Bcl-xL maintains a fully functional immune system that ensures an efficient clearance of senescent cells. Moreover, there is a paradox, as inhibitors of Bcl-xL have been employed as senolytic agents, which have been shown to protect from aging in animal models.

Despite its well-documented anti-apoptotic role, Bcl-xL is also related to mitochondrial bioenergetics by modulating mitochondrial fusion and fission, increasing total mitochondrial biomass, and enhancing the efficiency of the ATP synthesis. As cellular senescence can be both beneficial and detrimental for the organism, accordingly, Bcl-xL might play a dual role on senescence.

A possible hypothesis could be that during acute senescence, Bcl-xL effects on mitochondria would help senescent cells to cover their metabolic demand to secrete the SASP to promote their clearance as part of the senescence-clearance-regeneration procedure. However, senescent cells are also characterized by dysfunctional mitochondria, due to an imbalance between mitochondrial fission and fusion, which is critical for the functionality of the mitochondrial network. In this scenario, Bcl-xL might avoid the accumulation of dysfunctional mitochondria in senescent cells, thus preventing their detrimental effect on tissue homeostasis.

Senescent cells mainly depend on the immune system to be cleared; thus, a dysfunctional immune system will lead to accumulation of senescent cells within tissues. To promote the depletion of senescent cells, senolytic drugs aim to eliminate senescent cells without affecting quiescent or proliferating cells. Since the expression of anti-apoptotic and pro-apoptotic genes is higher in senescent cells compared to healthy cells, inhibitors of Bcl-xL have been described as senolytic agents because they only induce apoptosis in senescent cells, both in vitro and in vivo. ABT737, ABT263 or Navitoclax, which targets the Bcl-2/Bcl-xL proteins, is a potent senolytic drug that selectively kills senescent cells, regardless of how they were induced.

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