The average human lifespan is now almost twice as long as it was in the previous century. Nevertheless, serious illness or death of a loved one ranks among Americans’ top 10 fears of 2018. These fears are warranted given that every 65 seconds someone in the U.S. develops Alzheimer’s disease. Despite living longer, we are not necessarily living healthier.

A whopping 46 million Americans are currently over 65 years of age. Aging is the greatest risk factor for Alzheimer’s disease. Other known risk factors include family history of the disease, genetic mutations, head injuries and cardiovascular disorders. A phenomenon called cellular senescence, previously identified as a culpable cause of aging and age-related disorders, was recently implicated in Alzheimer’s disease for the first time.

What is cellular senescence?

Senescence literally means “to grow old”. So it’s surprising that cellular senescence is actually our body’s anti-cancer mechanism.

Stresses such as radiation exposure, oxidative stress, irreparable DNA damage and metabolic dysfunction can induce cellular senescence. Senescent cells are damaged cells that are placed under lockdown and prevented from dividing. This ensures that the damage is not passed on to future cell generations of cells.

Since they are no longer useful to the organism, senescent cells should be and often are destroyed by the body’s immune system. To help the immune system identify them, these cells enter the senescence-associated secretory phenotype and release pro-inflammatory signals. If all goes well, the senescent cells are destroyed by immune cells flagged to the site by the inflammatory molecules.

Senescence is derived from a Latin word that means “to grow old”. Senescent cells undergo cell cycle arrest and enter a zombie-like undead state. They are prevented from dividing into new cells but do not die. Photo by Melissa Mjoen on Unsplash.

As we age, senescent cells appear to escape immune surveillance. As more cells continue to undergo cell cycle arrest with age and fail to be cleared by the immune system, senescent cells accumulate over the lifespan of an organism. They persist in an altered “zombie”-like undead state – neither reproducing nor functioning optimally. To make matters worse, the maelstrom of inflammatory signals that they continue to secrete act as stressors for neighboring cells, leading to a “zombie apocalypse” that turns nearby healthy cells senescent.

The evidence for zombie cells in the brain

The brain consists of many different cell types that work together to ensure brain health and efficiency. Neurons are the wiring system of the brain, allowing communication between different parts of the brain via electrical impulses. Neurons do not divide and regenerate, so it is difficult to replace them when they are damaged. Other more rapidly dividing cell types, like astrocytes and microglia, therefore take on the role of nourishing the neurons and protecting them from damage.

Stress and aging lead to accumulation of “zombie” astrocytes and microglia in the brains of rodents and humans. These “zombie cells” can be told apart from healthy non-proliferating cells based on their unique signatures of arrested cell growth (characterized by telomere shortening and expression of cell cycle inhibitors p16/p21) and inflammation.

In 2012, researchers demonstrated that neurons from aged rodents were marked by more inflammation and senescence-like protein expression. These “zombie” neurons were less efficient because of impaired neurotransmitter production (chemical messengers of the brain) and fewer connections with other neurons. Although these observations led to speculation that cellular senescence may play a role in neurodegenerative diseases, up until very recently there was no direct evidence of this.

T cell attacking a cancer cell. Credit: Meletios Verras.
T cell attacking a cancer cell. Credit: Meletios Verras.

The zombie apocalypse of neurodegenerative diseases

A study published recently in Aging Cell investigated the role of cellular senescence in neuron loss associated with Alzheimer’s disease in humans.

The brains of Alzheimer’s patients are rife with neurofibrillary tangles containing abnormally modified tau proteins. As disease severity worsens, the number of these tangles also increases. Tau tangles are also reported in over 20 other neurodegenerative diseases including progressive supranuclear palsy and Parkinson’s disease.

Researchers at the University of Texas Health Sciences Center at San Antonio set out to investigate whether abnormal tau accumulation triggers cellular senescence, ultimately leading to the loss of brain cells and chronic dysfunction.

How did they test this hypothesis? Tau tangle-containing neurons were obtained from Alzheimer’s patients post-mortem and compared to normal neurons from the same patients. Tangle-containing neurons showed elevated expression of cellular senescence genes.

Strike one.

They also tested their hypothesis in genetically modified mice over-expressing either normal or mutant human tau protein and compared them to “control” mice that did not express tau. Similar to human brain tissue, tau tangle-containing mouse neurons had elevated expression of senescence-associated genes and inflammatory mediators, as compared to neurons from control mice.

Strike two.

To pin down tau tangles as the zombie creator, another genetically modified mouse line was used. These mice expressed amyloid plaques – another characteristic feature of Alzheimer’s disease pathology. Mice that showed heavy amyloid deposition in their neurons but no tau tangles did not have elevated expression of senescence markers. Furthermore, neurons obtained from post-mortem tissue of patients with progressive supranuclear palsy – another neurodegenerative disease characterized by tau tangle formation – showed senescence-related results consistent with those of Alzheimer’s patients and transgenic mice.

Strike three.

Pathological phosphorylation (yellow) of Tau proteins (red-orange) leads to disintegration of microtubuli in the neuron axon and aggregation of the tau proteins. The transport of synaptic vesicles (orange-blue) is interrupted. Credit: selvanegra.

Fighting the zombie apocalypse with senolytics

Now that we know a probable cause of the zombie apocalypse, or cellular senescence, in the brain, can we design an effective antidote against it? “Senolytics” are drugs that specifically eliminate senescent zombie cells. Dasatinib and quercetin are some of the well-characterized molecules in this class of drugs. Dasatinib is an FDA-approved drug used to treat leukemia. Quercetin is a plant flavonoid found in a variety of fruits and vegetables including apples, berries, green leafy vegetables, onions and tea.

To determine whether senolytics can reduce Alzheimer’s disease-related pathology, aged mice with tau tangles in their brains were treated with a combination of dasatinib and quercetin twice a week for three months. This treatment reduced tangle-containing neurons and senescence-related gene expression in these mice compared to those that did not receive the drugs. Importantly, the drug cocktail also reduced (but did not completely prevent) loss of neurons.

Past drug development efforts for Alzheimer’s disease have been riddled with failures. One reason for failure was that most of these experimental drugs needed to be administered to patients in the very early stages of the disease and only led to minor behavioral improvements. The new senolytic treatment results in mice seem promising because they seem to work in aged animals at advanced stages of the disease.

Dasatinib has previously been used to treat certain central nervous system tumors, suggesting that it can cross the blood-brain barrier. Amount of dasatinib reaching the brain can be boosted by co-administration with quercetin, which blocks transporters that actively pump dasatinib out. Nonetheless, till these drugs are systematically tested in large clinical trials and show marked cognitive benefits, we can only remain cautiously optimistic.

Is it possible, however, to get the benefits of senolytics through other means? Can lifestyle interventions reverse or slow cellular senescence?

Senolytics are a class of drugs that specifically eliminate "zombie" cells from tissues. Plant-based foods such as berries, apples, and citrus fruits are rich in anti-oxidants and are also a source of senolytics such as quercetin. Photo by Danielle MacInnes on Unsplash.
Senolytics are a class of drugs that specifically eliminate “zombie” cells from tissues. Plant-based foods such as berries, apples, and citrus fruits are rich in anti-oxidants and are also a source of senolytics such as quercetin. Photo by Danielle MacInnes on Unsplash.

Evidence-based interventions to prevent zombie cells from taking over your brain

1. Diet

Obesity is a risk factor for numerous age-related diseases including diabetes, stroke, cancer and Alzheimer’s disease. Processed foods and a calorie-rich, nutrient-deficient fast food diet results in visceral fat deposition around the internal organs and contributes to chronic low grade inflammation. In addition, metabolic syndromes such as insulin resistance hamper glucose utilization and energy production in the brain, impair elimination of toxic amyloid proteins and lead to accumulation of tau tangles.

Dietary modifications can positively impact health and longevity. In one study, genetically modified mice that experience accelerated aging due to cellular senescence were subject to intermittent fasting (alternate day fasting for 24-hours, the equivalent of at least a multi-day fast for humans) for 8 weeks. Expression of senescence-associated markers was lower in fasted mice. These mice also expressed higher levels of a neuronal growth factor, indicating that intermittent fasting may prevent age-related decline in brain health (at least in mice).

Phenylindanes in Brewed Coffee Inhibit Amyloid-Beta and Tau Aggregation:
Phenylindanes in Brewed Coffee Inhibit Amyloid-Beta and Tau Aggregation:

Editor’s note: A new study published this month reveals mechanisms by which certain compounds found in particularly dark roast coffees, called phenylindanes, can help inhibit tau aggregation!

Editor’s note on fasting for brain health: Time-restricted feeding has also been shown to clear abnormal proteins from the brains of mice. We don’t yet know if intermittent fasting in humans can effectively help clear senescent cells and abnormal protein aggregates from the brain, but fasting along with an anti-inflammatory diet may realistically help control levels of inflammation and reduce insulin resistance, both potential contributors to brain injury with neurodegenerative diseases. According to neuroscientist Mark Mattson, “Fasting is a challenge to your brain […] your brain reacts by activating adaptive stress responses that help it cope with disease.” Some individuals, however, may need to be cautious with fasting, particularly extended fasts. Fasting in conjunction with exposure to certain neurotoxins (like those found in pesticides) that damage the mitochondria in brain cells could create an “energy crisis” in these cells and promote neuronal death, for example. Fasting recommendations should take into account environmental exposures and nutrient needs of the individual.

2. Exercise

Along with a balanced diet, exercise is essential in preventing obesity and age-related diseases. The U.S. Department of Health and Human Services recommends at least 30 minutes of moderate-intensity physical activity 5 times per week for healthy adults.

Senescence and inflammatory markers were found to be elevated in visceral fat of mice fed a high fat diet. Exercise completely blocked diet-induced accumulation of senescent cells in these mice. Whether exercise prevents accumulation of senescent cells in Alzheimer’s disease has not been tested. However, physical activity can delay the onset of Alzheimer’s disease and reduce the risk of cognitive decline. This could be due to improved blood flow and neuronal activity in areas of the brain involved in memory formation and storage.

3. Sleep

For optimum health, the American Academy of Sleep Medicine and Sleep Research Society recommends 7 or more hours of sleep regularly for adults.

Emerging evidence shows that partial or chronic sleep deprivation can increase one’s chances of developing Alzheimer’s disease. Sleep deprivation led to accumulation of amyloid protein in the brains of healthy human volunteers. Accumulation of insoluble amyloid plaques is a hallmark of Alzheimer’s disease.

Could lack of sleep lead to cellular senescence? DNA damage and a gene expression profile reminiscent of senescent zombie cells was reported in older adults with partial sleep deprivation, who only slept for 4 hours during the early morning hours. Similarly, mice subject to chronic sleep deprivation had higher expression of inflammatory mediators in their brains. So when it comes to your brain, sleep over it.

Tips from the CDC for a good night’s sleep:

  • Go to bed at the same time each night and get up at the same time each morning, including on the weekends.
  • Make sure your bedroom is quiet, dark, relaxing, and at a comfortable temperature.
  • Remove electronic devices, such as TVs, computers, and smart phones, from the bedroom.
  • Avoid large meals, caffeine, and alcohol before bedtime.
  • Avoid tobacco/nicotine.
  • Get some exercise. Being physically active during the day can help you fall asleep more easily at night.

A healthier lifestyle leads to a healthier you. Take control today!