Senescent Cells and Alzheimer's Disease

Aging is the main risk factor for Alzheimer's disease (AD). We do not yet know why aging makes people more vulnerable to AD. One possibility is a process called "cellular senescence." This happens when cells stop growing or dividing. Senescence leads to inflammation that damages cells.¹

Higher levels of senescent cells (SCs) may be common in brains of people with AD. We do not know whether SCs are a cause or result of AD. But removing SCs may affect other AD processes and improve memory. This is why scientists are studying whether removing SCs can treat AD.²

What are senescent cells?

SCs are living cells that no longer grow or divide into new cells. This state of permanent non-dividing is called "cellular senescence." Cellular senescence happens because of damage to the cell. Cells switch to this non-dividing state to prevent cell death.¹

Cellular senescence is a normal part of development, wound healing, and tumor prevention. In this way, it helps maintain stability in response to changes in our environment. But chronic senescence can lead to cell damage.^1,3

When they become senescent, cells enter a highly inflammatory state. SCs release inflammation chemicals. These chemicals trigger the immune system to clear the senescent cells. High levels of SCs can lead to chronic inflammation. This inflammation can damage nearby cells and the whole organism.²

What role do senescent cells play in aging?

Cellular senescence is a normal part of aging that cannot be avoided. This is because cell damage accumulates over our lifetime. The term "senescence" also refers to the general biological process of aging.^1,2

As we age, SCs build up faster than the immune system can clear them. This leads to chronic inflammation and cell decline. Our cells no longer respond to stress and damage well. This leaves them more vulnerable to age-related conditions.^1,2

How are senescent cells involved in Alzheimer's disease?

Aging is the main risk factor for AD and other neurodegenerative conditions. So it makes sense that SCs play a key role in AD. Indeed, people with AD seem to have higher levels of SCs in the brain. This may be because biological processes that lead to AD also trigger brain cell senescence. For example:^2,4-6

• Amyloid beta deposits trigger senescence of many types of brain cells
• Buildup of tau proteins leads to senescence of neurons

However, we do not know if senescence is a cause or a result of aging and AD. It may be that AD leads to higher levels of SCs. On the other hand, high levels of SCs may lead to symptoms of AD. For example, the inflammation caused by cellular senescence may lead to cell decline. But anti-inflammatory drugs do not have any effect in AD. So it seems like inflammation is a result of AD, not a cause.²

On the other hand, people with AD may have a higher genetic risk of cellular senescence. This means people with AD may be more vulnerable to SCs. This may explain how AD develops in certain older people.²

How can we target senescent cells to treat Alzheimer's disease?

Studies have shown that clearing SCs from the brain can slow cognitive decline. Clearing SCs may reduce other processes involved in AD, such as buildup of tau protein. This is why scientists are targeting SCs to treat AD and other age-related conditions.^2,5

When cells become senescent, they become more resistant to cell death. This is to protect themselves from their damaging inflammatory environment. SCs use certain pro-survival pathways. Interfering with these pathways can specifically kill SCs.²

Drugs that selectively clear SCs are called senolytics. Examples of senolytic chemicals include:^5,7,8

1. Dasatinib
2. Quercetin
3. Fisetin
4. Navitoclax

Early studies in mice have shown the promise of these drugs in treating age-related conditions. But there have not yet been any clinical trials to show how well they work in humans.^2,5,8