Human Longevity: How Senolytic Drugs could Overturn the Graveyard of Failed Alzheimer’s Disease Treatments
It’s an army. Not one of soldiers, but scientists. The world’s brightest researchers, equipped with billions in funding and the most cutting-edge technology in the world, set off to treat Alzheimer’s disease (AD). Though they dedicate their entire lives to the research and treatment of AD, failure is the outcome (wait but why?).
Between 2000 and 2012, 244 compounds were tested in 433 clinical trials as potential treatments for Alzheimer’s.
One compound was approved.
As for the other 243…
It’s a tragedy. It’s more than a tragedy, it’s a scandal. We don’t even know whether the drugs are any good. That is true of every trial that’s been conducted in Alzheimer’s.
Those were the words of Simon Lovestone, director of the U.K. NIHR’s Dementia Biomedical Research Unit at King’s College, 5 years ago. Since then, we’ve still seen minimal progress.
A History of High Hopes and Failure — Why?
The Origin Story of Alzheimer’s Disease.
Dr. Alois Alzheimer had no choice in getting the disease named after him.
In 1901, this German psychiatrist met Auguste Deter. Her husband had noticed her increasing memory problems, accompanied by elevated fear, aggression and paranoia. This escalation warranted a visit to the psychiatric hospital, where Auguste remained until her death — at age 55.
When Dr. Alzheimer microscopically examined Auguste’s brain postmortem, his examination revealed the existence of two things: amyloid plaques and neurofibrillary tangles. His senior colleague, Emil Kraepelin, suggested he had discovered a new disease and named it Alzheimer’s Disease (AD). This discovery kicked off a centuries-long research effort to understand, treat, and cure AD.
The Disease Itself, and its Progression
Alzheimer’s disease begins innocuously. We’ve all experienced forgetting a name here or there, or maybe reading a paragraph and realizing we have no idea what we just read. These are features of early stage Alzheimer’s, a stage characterized by brief memory lapses. Nevertheless, the individual can still function independently day-to-day.
Yet, as we irreversibly slip into moderate stage Alzheimer’s, these memory slips begin happening too frequently to be normal. In this stage, such thoughts become not uncommon:
“When did I get married? I don’t remember what happened on the ‘happiest day of my life.’”
“Where am I? Whose house is this? I swear this isn’t mine. It’s not mine. It can’t be.”
“Did I just wet myself?”
“I’ve always known my siblings aren’t any good. They’re out to get me. Is it money they want? Right, that’s it. They’re trying to poison me for my money.”
These thoughts, emotions, and personality changes can plague the individual for years. Moderate-stage Alzheimer's is the longest stage, characterized by difficulties expressing thoughts, uncharacteristic and aggressive behaviour, and the inability to perform routine tasks without assistance. It often ends with the need for outside care in a professional facility.
This professional care, which may have started off as an occasional visit, can quickly become round-the-clock 24-hour care in late-stage Alzheimer’s. By this time, the individual is numb to their environment. Unresponsive. Even communicating pain can be extraordinarily difficult.
Given the progressive, irreversible nature of the disease, it’s tragic yet unsurprising what follows—death, usually due to complications of neurological decline.
Explanations on Why Alzheimer’s Occurs
The two leading theories in the field stem from Dr. Alzheimer’s examination and discovery of amyloid-beta plaques and neurofibrillary tangles. They are the amyloid hypothesis and tau hypothesis.
Understanding Alzheimer’s through the Amyloid Hypothesis
A quick rundown: Plaques gradually form in the brains of patients with AD, weakening neural connections and causing memory loss and other AD symptoms.
The in-depth science: It all begins with a protein called amyloid precursor protein (APP). Typically, APP directs cell migration during brain development. But then, two enzymes show up…
β-secretase and γ-secretase are enzymes that serve as scissors to cleave APP. When they cut up the amyloid precursor protein, a molecule called β-amyloid is generated. In the diagram, it’s the orange cloud-looking blob.
β-amyloid has a tendency to misfold and stick to other clumps, forming chains called oligomers. These oligomers will clump up into fibres, which then gradually clump up into plaques. They’ll weaken neural communication and connectivity at synapses (junctions between neurons), leading to memory slips and loss.
In summary:
- Amyloid precursor protein (APP) exists (to help with neurodevelopment)
- APP is cleaved by two enzymes, β-secretase and γ-secretase
- When APP is cleaved, we get a molecule called β-amyloid
- β-amyloid misfolds and clumps into plaques
- Plaques reduce neural connectivity and cause memory loss symptoms
This is the amyloid hypothesis, and it’s one of the leading theories in the field today. But there are still so many unanswered questions — the tau hypothesis might be able to paint a fuller picture.
Understanding Alzheimer’s through the Tau Hypothesis
A quick rundown: Tau is a protein normally responsible for stabilizing the structure of neurons. However, in Alzheimer’s disease, tau separates and begins clumping up into neurofibrillary tangles—the ones Dr. Alzheimer observed. Without tau providing structural support, the neuron eventually dies.
The in-depth science: Much like how humans need a skeleton, so too do neurons. Neurons have a cytoskeleton, which is formed by three fibres: microfilaments, microtubules, and neurofilaments. They work together to give the neuron structure, allowing for cell division, strength and structure, and muscle movement.
Microtubules are especially important because they facilitate communication between microfilaments and neurofilaments. Tau is the protein that allows these crucial microtubules to remain stable.
However, in Alzheimer’s disease, tau is modified, adopting an abnormal shape and disassociating from the microtubule it’s supposed to support. The separated proteins will stick together, forming neurofibrillary tangles. With its structural support gone, the neuron gradually dies.
In addition to killing the neuron that the tau protein separated from, neurofibrillary tangles can even spread to healthy neurons, causing its healthy tau protein to begin misfolding as well. The spread of tangles correlates perfectly to the increasingly severe symptoms we see in Alzheimer’s disease.
Bringing it all Together
The amyloid hypothesis and tau hypothesis aren’t mutually exclusive theories of AD’s pathology. In conjunction, plaques and tangles can wreak havoc on the brain of an AD patient.
The presence of β-amyloid plaques reduces neural connectivity and eventually causes neuronal death. This damage is compounded by the existence of neurofibrillary tangles, which harm the cellular mechanisms that the neuron needs to survive.
For the longest time, the majority of research efforts have focused on eliminating either plaques, tangles, or both. The solution sounds logical — remove what’s causing damage and the damage will reverse itself. Yet, the crushingly disappointing 99.6% failure rate is forcing us to confront an extremely uncomfortable truth — what if they’re wrong?
It’s Time for New Approaches
As the world population ages exponentially, our vulnerability to Alzheimer’s disease only increases. And with the healthcare cost of treating AD rapidly spiralling to the trillion-dollar mark, we need something that works.
Even though the majority of research efforts have focused on eradicating β-amyloid plaques or misfolded tau tangles, they’ve yielded minimal results. It’s time for a new approach, and the answer might just be found in senolytic treatment.
Hang on, what are Senolytics?
To answer that, let’s first understand cellular senescence. Cellular senescence is a process of aging (happening inside you right this second) that occurs when healthy cells stop proliferating and instead become “zombie cells.” They’re not quite dead, but don’t perform their designated job either.
The role of senescent cells is complex, and still not fully understood. On one hand, they encourage tissue repair and wound healing. But as you grow older, they accumulate and start exhibiting an opposite effect. They can send out inflammatory proteins that cause tissue dysfunction, encouraging neighbouring cells to become senescent as well.
The impact of cellular senescence is beautifully exhibited above. While there are certainly positives to senescence, such as tissue repair, they also lead to neurodegeneration, cancer, osteoporosis, and more.
OK, I thought this was about senolytics?
It is! Senolytics are drugs that selectively eliminate senescent cells. In an experiment that has been replicated many times now, researchers injected a sample of mice with senolytic drugs and left the control sample alone.
The treated mice had a decreased mortality rate by 35%, had thicker fur, stronger physical capabilities, and were healthier in general.
Of course, the implications of this are massive. What if senolytics could be given to humans? Would it reverse aging? Could it prevent neurodegenerative diseases? Currently, the relationship between Alzheimer’s and senescence is still murky, but a recent and exciting study is paving the path for a senescence approach to treating Alzheimer’s…
The Latest Research
In 2019, Dr. Mattson led a study that added substantial proof to the idea that senolytic drugs could rescue or alleviate memory loss in mice. The study aimed to:
- Understand the relationship between cellular senescence and AD
- If a relationship exists, use senolytic drugs to treat AD
Let’s break down the study and understand the researchers’ findings, as well as their experiment process.
Understanding the Relationship between Cellular Senescence x Aβ Plaque Buildup
To determine whether there was a correlation between β-amyloid plaques accumulation and the level of cellular senescence, the team examined three groups of patients. The first group had Alzheimer’s disease, the second group showed mild cognitive impairment, and the third group had no dementia at all.
In order to examine the levels of β-amyloid plaque deposits and senescent cells, the researchers took brain tissue from the parietal cortex of these patients. They then immunostained the tissue samples, a technique that allows researchers to detect levels of the proteins they’re looking for. In this case, they were looking for Aβ deposits, as well as two senescence biomarkers called Olig2 and p16.
After immunostaining the brain tissue of all three groups of patients, these were the results:
They found a positive correlation between the amount of β-amyloid load and the amount of senescent cells. Patients with AD showed the highest amount of β-amyloid plaques and senescence, while patients with MCI showed less, and patients with no dementia showed hardly any at all.
After identifying this positive connection, the team decided to test whether eliminating these senescent cells could improve brain function.
Treating AD in Mice with a Senolytic Drug Cocktail
In order to model the pathology of Alzheimer’s disease, the researchers genetically engineered a group of mice to accumulate β-amyloid plaques (AD doesn’t naturally occur in mice).
As the plaques aggregated, they induced cellular senescence in a specific subtype of glial cells: oligodendrocyte progenitor cells (OPCs). Normally, OPCs are responsible for myelin regeneration and ensuring neural communication goes smoothly. However, the plaques caused these OPCs to become senescent and turn to the dark side, spewing out inflammatory proteins to encourage senescence in its surrounding OPCs.
They now had a target — senescent OPCs.
Next, the researchers whipped up a senolytic drug cocktail of dasatinib + quercetin, two FDA-approved senolytic compounds touted as the golden child of anti-ageing drugs.
They administered this dose of D+Q to a treatment group of mice weekly for 11 weeks, measuring their memory and cognitive performance at the beginning, middle and end of those 11 weeks. The researchers compared the treatment group’s results to the control group of mice, who did not receive any D+Q treatment.
The results by the end of the 11 weeks were fascinating.
First of all, pictured below is the hippocampi (the memory centre of the brain) of the control group versus the treatment group.
The top row shows the control group’s hippocampal tissue. Cellular senescence is indicated by the arrows and boxes. Now, compare those levels of senescence to that of the treatment group, in the bottom row. The treated mice have far fewer senescent cells!
What’s more, when the mice had to run mazes, the researchers found that treated mice performed “significantly better” than untreated mice. Overall, eliminating senescent cells had protected vulnerable neurons in the hippocampus and cortex. It decreased β-amyloid plaques, reduced inflammation, and boosted memory.
TL;DR
To quickly summarize — the researchers identified a positive correlation between the amount of plaques and the amount of senescent cells. Then, they used a cocktail of senolytic drugs to eliminate the senescent cells in mice with AD. The result was that in the treated mice, levels of both β-amyloid plaques and senescence decreased, while memory and learning improved! In this study, senolytics had alleviated the symptoms of mice modelling Alzheimer’s disease.
Big Picture Significance
Now, full disclosure. This was only one study, modelling one type of Alzheimer’s disease. But, zooming out to examine the big picture, a pattern begins to emerge. For example, a previous study in 2018 also found that senolytic drugs alleviated memory loss symptoms in mice, once they eliminated senescent glial cells. This 2018 study targeted the tau hypothesis, demonstrating that senolytic treatment for mice with neurofibrillary tangles protected valuable neurons in the hippocampus.
The bottom line is that the senescence approach is new, and just taking off. While there is work to be done when it comes to applying these strategies on humans instead of mice, the potential impact of senolytics could be truly significant. In a research field plagued by failures, senolytics is a glimmer of hope.
In Closing
Thank you for taking the time to read this article! I’m downright fascinated by human longevity and it's potential to transform every aspect of life as we know it. Are you, too? If so…
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