Research Excellence

Targeting Senescence: Secrets to Postponing Alzheimer’s Disease

How Aging Neurons Prevent Us from Remembering

The world now has the largest population of elderly humans in its history. Age-related cognitive dysfunction, such as Alzheimer’s disease (AD), is becoming increasingly prevalent but no cure is currently available. AD is a major cause of patient disability that leads to significant psychological and economic burdens for patients’ families and has a significant public health impact. In China, for example, more than 7.4 million elderly adults live with age-related dementia. This population is expected to rise to 18 million by 2030 if no action is taken1. Figures from the United States show similar trends. Dr. Kim Chow, IAS Junior Fellow and Research Assistant Professor of Life Science at HKUST, is eager to better understand this alarming situation and tackle the disease from non-traditional angles.

\\  Despite 30 years of research into the disease mechanisms, there are no effective drugs to cure or stop the progression AD. \\

A Disease without a Cure Imposes a Public Health Crisis

AD is the most common form of age-related dementia, accounting for 60-80% of cases. It is a brain disease that causes a slow decline in memory, thinking, and reasoning skills. At the same time, it poses real challenges to patients’ family members, who must assume caregiving responsibilities. Feelings of incapacity, despair, weariness, and loneliness are common emotional burdens of caregivers2 that often affect their quality of life and their health. According to the US Centers for Disease Control and Prevention and the Alzheimer’s Association, AD is the most under-recognized public health crisis of the 21st century.

Chow emphasized that drug for AD is needed but 200 candidates had already been rejected. And even though the current drug pipeline might give us hope, a further 10-15 years will be needed for clinical trials and approval before any drug could go into the market. “How long can we wait for the miracle pill to come before the situation turns into a crisis? We need a parallel strategy so that everyone, not only the scientists and physicians, can contribute.” Chow explained that her research is focused on understanding how potential modifiable risk factors contribute to the development of AD. “By pinpointing the underlying molecular mechanism behind these risk factors, we may be able to target and prevent further harm to our brain.” Her goal is to find a way to delay the onset of AD, something everybody can play a part of, thus halving the apparent prevalence of the disease from a public health perspective. “No pharmacological interventions are able to show comparable effects,3” she said.

\\  A delay of onset by 5 years would halve the apparent prevalence of the disease. \\
Kim Chow's study seeks to find a way to delay the onset of Alzheimer's Disease

Insulin Resistance Promotes Cell Senescence

Researchers have long known that individuals who are insulin resistant (IR or pre-diabetic) have twice the risk of developing AD than healthy individuals, yet the molecular mechanism behind the link between IR and neuronal dysfunction in AD remains largely unknown. Chow had an answer to offer. “Chronic exposure of cells to abnormally high levels of insulin is the major cause of IR. Insulin is a hormone made by the pancreas that instructs insulin-sensitive cells like muscle and fat cells to absorb excess sugar in our blood. After meals, the cells in the pancreas sense a higher blood level of glucose, which triggers the pancreas to produce and release more insulin. Insulin reaches the muscle and fat cells through the circulatory system and signals them to absorb glucose, either to be used as fuel or to be transformed and stored as fat. IR refers to the condition in which these cells become less sensitive to insulin and thus require more insulin to remove excess blood sugar. Over time, exposure to high levels of insulin further desensitizes these cells to insulin. Consistent with the previous findings, we also found that neurons—the cells in the brain that fires electric currents in networks to form the basis of memories and cognitive function—are also insulin-sensitive. Although short-term exposure to insulin results in enhanced activity in these cells, chronic exposure results in unexpected cellular aging — stress-induced senescence.”

Cellular aging, or senescence, is a kind of stress-induced response4. There are two types of senescence response. One is called “replicative senescence”. This sets a limit to a cell for the number of times they can divide in a life time to avoid any inadvertent errors or mutations occurred during any cell division processes from passing on indefinitely5 . The second type is called “stress-induced senescence”. This usually happens when certain forms of stress, like a sudden turn-on of cancer-promoting genes or exposure to cancer-promoting chemicals (mitogens), attempt to trigger any uncontrolled cell division in a normal cell6,7. In this scenario, stressed-induced senescence kicks in to stop the cells from any further division. Indeed, stress-induced senescence is already indicated as part of the pathogenic loop in IR. This could be in part due to the fact that insulin is also a mitogenic hormone on top of its metabolic properties8.

Post-mitotic Neurons Can Also Age

Mature neurons are typically described as permanently post-mitotic in the cell cycle. Once they have grown functional units like networks of neurites and an axon, and have formed synapses, they do not return to a “pre-mature ground” state and divide. “In adult mice with naturally developed IR,” Chow said, “we found that substantial number of neurons (the area of the brain affected mostly in AD), showed positive markers of senescence, but other cell types did not. These cells showed an impaired firing response to stimuli and signs of IR.”

By definition, the pre-requisite of cellular senescence is a cell-dividing scenario. One vexing paradox then arises: how do mature neurons become senescent even though they are post-mitotic? Chow related that “many studies have reported substantial numbers of neurons in the brains of patients with AD that have undergone partial cell cycle re-entry. For some reason, these cells attempt to divide again but fail to complete the entire cell division process.” Previous studies did not explain how these afflicted cells could stay in the brain for years and decades and not die right away, or the pathological significance behind such a phenomenon. Chow is the first to explain that dividing neurons getting stuck in the middle of the cell cycle is, in fact, the process of cell senescence. “Using live cell imaging techniques, we demonstrated that chronic exposure to insulin triggered neuronal cell cycle re-entry before the senescence process. A substantial number of senescent neurons – a positive signs of cell cycle re-entry and IR – are observed in mouse models of AD. This is very encouraging because it suggested that chronic insulin-induced IR or any mechanism that fails the normal insulin signaling in neurons may introduce risks or even play a causative role of the disease. More importantly, IR is a modifiable condition that is manageable. This may imply a method to prevent AD in the future.”

The Zombie Apocalypse—Senescent Neurons Kill Their Neighbors

Chow explained, “we observed that these cells had a significant loss of neurites and other mature neurons markers. They also look flattened, a hallmark of senescent cells. Although one may think that these ‘degenerated’ cells do not contribute to the disease, an accumulating body of evidence shows that senescent cells have deleterious effects on the tissue microenvironment by acquiring a senescence-associated secretory phenotype (SASP) which turns a senescent neuron into a pro-inflammatory cell that has the ability to promote inflammation in the brain.”

“When we looked for potential signs of death in the senescent neurons in the brain tissues, we saw, to our astonishment, that only the neurons around the senescent cells were positive for cell death markers. With live cell imaging, we saw that senescent neurons were acting like zombies in a Hollywood movie, triggering the deaths of neighbors. We believe that this is an outcome of the SASP acquired by senescent neurons, as they revealed elevated expression of pro-inflammatory genes and proteins.” Chow is currently working on an unbiased spectrum-wide study to identify crucial factors released from senescent neurons. “We see that inflammation triggered by senescent neurons could be a potential starter of chronic neuro-inflammatory responses frequently observed in AD, which the latter contributes to the progression of the disease. If we could comprehensively characterize the molecular characteristics of senescent neurons using systems analyses, we could better understand these cells, and even identify potential targets, halt the SASP response, or even remove these cells specifically from the brain.

A Way to Reduce Risk Factors

Individuals with IR, type 2 diabetes and associated diseases such as obesity may have an increased risk of AD and similar conditions, such as vascular dementia9. Scientists have been mindful of these correlations, and Chow’s work has revealed the detailed molecular mechanisms behind this increased risk.

“Like many other age-related disorders, AD is a complex multifactorial disease. We understand that hyperinsulinemia and other features of the IR syndrome are associated with AD10. Although potential new therapies are not likely to come in a short time, modifiable risk factors like IR can be reduced by changes in lifestyle and diet, which can be done by anyone of us, and thus the risk of AD can be reduced. Educating the public can be easily done to increase the awareness of AD. I believe that everyone is responsible for their physical well-being and should play a part in this long-lasting battle.”

Seeking Resources and Policy Support

For her latest findings, Chow was recently awarded the 2017 L’Oreal-UNESCO-China Association for Science and Technology of the Rising Star of For Women in Science National Fellowship in China. In addition to the RGC grant she received in 2017, she has also received an Alzheimer’s Association Research Fellowship. These funds will support her research in AD. “We remain hopeful that we can achieve a better understanding of the disease and win this long battle. It is not going to be easy but we, as scientists, have an obligation to learn from our failures, listen to the data and stay open-minded at all times.”

\\  Scientists have the obligation to learn from our failures, listen to the data and stay open-minded at all times.  \\

Chow is currently a Global Research Council Fellow of the World Economic Forum. Along with thought leaders from academia, government, business sector, and civil society at the Council of the Future Neurotechnologies and Brain Science, she took part in the intense exercise at the annual Dubai meeting in November 2017, to identify global brain health areas with the greatest unmet needs, in the hope that these issues can be brought to the policy level in the Davos meeting.

Research: A Lifelong Learning Process

To many people, finishing a doctoral degree means a full stop in the active learning process, but to Chow, every day means a new day of learning. “I always feel that I have not learned enough. We all want success and breakthroughs, but wanting is not enough. One must hunger for it.” With new technologies, Chow sees the necessity for rapid adoption to leverage benefits. Big data, systems approaches, and mathematical and computational modeling, for instance, are tools available outside the traditional research approaches that could give quick, precise answers to complex questions. “While learning is important, I believe there are no more one-man bands in today’s research. Fostering collaboration among specialties is a key to success.”

A recent project on another neurodegenerative disease called Ataxia-telangiectasia has given Chow an opportunity to analyze systematically the overall molecular features of mutated cells and a quest to model the disease from both computational and mathematical perspectives. Given the greater capability with the latest technologies, scientists can move from focusing on areas that interest them, to a more holistic analysis. “With new data and techniques emerging with an unimaginable speed every day, there is no reason for me to stop learning to participate in this exciting era.”