Researchers have found that, unusually, entering a senescent state actually improves some measures of performance in the beta cells of the pancreas responsible for producing insulin. Senescent cells are those that have removed themselves from the cycle of replication, either because they have reached the Hayflick limit, or prior to that point in reaction to molecular damage or a toxic local environment. A senescent cell may destroy itself via programmed cell death mechanisms or it may be destroyed by the immune system, but while it remains in place it behaves badly, secreting a harmful mix of molecules that change surrounding cellular behavior and remodel tissue structures. Aging brings a growing number of these senescent cells in all tissues, lingering long past the point at which they should have been destroyed. Their harmful effects grow sizable and contribute to the pathology of most age-related conditions. Thus cellular senescence is a cause of aging, age-related disease, and death. Even if all of the other mechanisms that cause aging were hand-waved away, increasing numbers of senescent cells alone would be enough to kill us eventually.
Biology is complex, however, and it is rare for any given process to do just one thing, or for any mechanism to be important in just one way. Evolution likes reuse, and cellular senescence has a variety of forms and has evolved into a variety of roles. It may have started as a process of embryonic development, a way to halt growth in order to define the shape of extremities such as fingers. The transient creation of senescent cells is also involved in wound healing, however, and senescence in response to damage and toxins likely serves to reduce the risk of cancer, or at least initially. Large numbers of senescent cells cause significant chronic inflammation, among other issues, and that eventually overwhelms any cancer-prevention benefit resulting from preventing replication in cells at a greater risk of suffering cancerous mutations.
Given all of this, it shouldn't be completely surprising to find more places and circumstances in the body in which cellular senescence produces benefits along the way towards ultimately helping to kill us. That we find such benefits isn't a good reason to pull back from efforts to produce therapies that can clear senescent cells from the body, and thereby prevent their contribution to aging, of course, but they do serve to remind us that nothing is ever simple when it comes to living organisms.
New research shows that a cellular program that causes aging can also bring unexpected benefits in the function of pancreatic beta cells and the production of insulin in mice and humans. The researchers examined the activity of a gene named p16, which is known to activate a program called senescence in cells. Senescence prevents cells from dividing, and is therefore important in preventing cancer. The activity of the p16 gene increases in human and mouse pancreatic beta cells during aging and limits their potential to divide. This activity is thus seen as having a negative effect - the lack of ability of these cells to divide can contribute to diabetes, since beta cells are the cells responsible for secreting insulin when blood glucose levels are high, and their loss causes diabetes. However, it was unknown whether senescent beta cells could continue functioning at all.
To their surprise, the researchers discovered that during normal aging, p16 and cellular senescence actually improve the primary function of beta cells: the secretion of insulin upon glucose stimulation. Because insulin secretion increases during the normal aging of mice and is driven by elevated p16 activity, some of these cells actually start to function better. The researchers further found that activation of p16 and senescence in beta cells of mice that suffer from diabetes enhanced insulin secretion, thereby partly reversing the disease and improving the health of the mice. Similar experiments conducted in human cells strongly suggest that senescence-induced enhancement of insulin secretion is conserved between mice and humans, and point to the p16 gene as its main driver in both organisms.
Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16Ink4a is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16Ink4a in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit.
Expression of p16Ink4a in beta cells induces hallmarks of senescence - including cell enlargement, and greater glucose uptake and mitochondrial activity - which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16Ink4a activity. We found that islets from human adults contain p16Ink4a-expressing senescent beta cells and that senescence induced by p16Ink4a in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16Ink4a and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.