Necroptosis is a form of regulated cell death that shares characteristics with both apoptosis and necrosis. It is a backup mechanism that allows the body to eliminate damaged or infected cells when apoptosis is blocked or impaired. Unlike apoptosis, it results in the rupture of the cell membrane and the release of its contents, triggering a strong inflammatory response. This makes it a double-edged sword: it is useful for fighting infections and eliminating dangerous cells, but when uncontrolled, it can contribute to tissue damage, chronic inflammation and age-related diseases.
Necroptosis has attracted growing attention in aging and longevity research because it plays a role in neurodegeneration, cardiovascular disease, autoimmune conditions and metabolic dysfunction.
How necroptosis works
Necroptosis is initiated when the body activates certain immune receptors, typically in response to viral infection, cell stress, or toxic damage. If the cell’s apoptotic machinery (particularly caspase-8) is unavailable, the death signal is diverted toward the necroptosis pathway, which is controlled by a series of proteins including RIPK1, RIPK3 and MLKL.
Once activated, these proteins create pores in the cell membrane, leading to its rupture. The cell’s contents spill into the surrounding tissue, where they can alert the immune system and amplify inflammation. This process is part of a group of cellular events known as immunogenic cell death, which not only removes the damaged cell but also sends danger signals to the rest of the body.
Necroptosis and disease
Because necroptosis releases inflammatory molecules, it is strongly implicated in inflammatory and autoimmune diseases. In conditions like multiple sclerosis, inflammatory bowel disease and lupus, necroptosis contributes to a cycle of cell death and immune activation that worsens tissue damage. In neurodegenerative diseases like Alzheimer’s and Parkinson’s, it may drive the progressive loss of neurons by activating harmful immune responses in the brain.
It also plays a role in heart disease, particularly in ischemia-reperfusion injury, where sudden reoxygenation of tissue triggers oxidative stress and inflammatory cell death. In these settings, targeting the necroptosis pathway is being explored as a therapeutic strategy.
Necroptosis and aging
With age, the body experiences increasing levels of low-grade, chronic inflammation, a process often referred to as inflammaging. Necroptosis may be one of the sources of this inflammation. As cells lose the ability to undergo clean apoptosis, they are more likely to enter necroptosis, spilling inflammatory content into surrounding tissues and driving systemic aging.
This mechanism may also contribute to age-related decline in immune function, where increased cell death and tissue stress provoke excessive or misdirected immune responses. Researchers are now studying how inhibiting it might help preserve tissue function and reduce age-related inflammation.
How to regulate or limit it
Though we don’t yet have widely available therapies that specifically block necroptosis, researchers are developing drugs that inhibit key proteins in the pathway, particularly RIPK1 and MLKL. In the meantime, supporting cellular health and inflammation control may help reduce unnecessary necroptotic activity.
- Anti-inflammatory diets rich in omega-3s, antioxidants and polyphenols may lower triggers;
- Exercise helps maintain immune balance and may reduce chronic activation of necroptotic pathways;
- Stress management, sleep quality and metabolic health are also crucial for keeping inflammatory signaling in check.
Keeping cellular stress and immune overactivation under control may indirectly reduce necroptosis in aging tissues.
Necroptosis is a powerful cellular process that can both protect and harm the body, depending on the context. While it helps eliminate infected or damaged cells, excessive necroptosis contributes to chronic inflammation, tissue degeneration and aging. Understanding how it works and how to modulate it, offers promising insights into slowing inflammatory aging, preserving organ function and improving resilience in later life.
