Slowing, let alone reversing, the process of ageing was once alchemical fantasy. Now it is a subject of serious research and investment. Peter Thiel, a co-founder of PayPal, Larry Page and Sergey Brin, co-founders of Google, and Jeff Bezos, founder of Amazon, have all invested in, and often been instrumental in the creation of, firms trying to prolong lifespan and healthspan. In March Sam Altman, the head of OpenAI, revealed that two years ago he had invested 180m in Retro Biosciences, a Silicon Valley firm founded with the goal of adding ten years to healthy human lifespans.

Beneath the forest canopy of firms backed by tech royalty an undergrowth of more conventionally financed startups is working on drugs that might slow or stall some aspects of ageing. Even closer to the ground, the idea is catching on of prolonging lifespan and healthspan using pills and potions that are already available, in addition to (and sometimes instead of) the conventional approach of diet, exercise, and early-to-bed. A culture of do-it-yourself lifespan extension is emerging, at least in affluent places endowed with the sort of technical expertise and technological hubris identified with Silicon Valley.

Many in mainstream science and medicine look at all this slightly askance. That is understandable. It is an area which attracts chancers and charlatans as well as those with more decent motives, and its history is littered with "breakthroughs" that have led more or less nowhere. America's Food and Drug Administration does not recognise "old age" as a disease state, and thus as a suitable target for therapy. Nevertheless, evidence has been accumulating that such research might have something to offer.

Some established drugs really do seem to extend life, at least in mice. That offers both the possibility that they might do so in people and some insight into the processes involved. The ever-greater ease with which genes can be edited helps such investigations, as does access to large amounts of gene-sequence data. The ability to produce personalised stem cells, which stay forever young, has opened up new therapeutic options. And new diagnostic tools are now offering scientists means to calculate the "biological ages" of bodies and organs and compare them with actual calendar ages. In principle this allows longevity studies to achieve convincing results in less than a lifetime.

Another reason for hope is that the physiological details of ageing are becoming clearer. In particular, those researching the question have been able to divide the problem into bite-sized chunks that can, to some extent, be tackled individually. Researchers have proposed 12 hallmarks of ageing chosen on the basis that they are all things which typically get worse with age, which accelerate ageing if stimulated and which seem to slow it down if treated. Some of these smaller (if often still huge) problems are attractive targets for intervention in their own right; chronic inflammation, for example, or the build-up of aberrant proteins seen in Alzheimer's disease. George Church of Harvard University, a biotech guru unafraid of the unorthodox, thinks the approach could offer more than that: identify and deal with each of the components separately and you may find you have solved the problem in its entirety.

For most of our history, even getting to old age was a significant accomplishment - and while centenarians have been around at least since the time of the Greeks, aging was never of major interest to medicine. That has changed. Longevity medicine has entered the mainstream. First, evidence accumulated that lifestyle modifications prevent chronic diseases of aging and extend healthspan, the healthy and highly functional period of life. More recently, longevity research has made great progress - aging has been found to be malleable and hundreds of interventional strategies have been identified that extend lifespan and healthspan in animal models. Human clinical studies are underway, and already early results suggest that the biological age of an individual is modifiable.

A concerted effort has been made in the longevity field to institutionalize the word "healthspan". Why healthspan (how long we stay healthy) and not its side-effect of lifespan (how long we live)? The reasons are linked more to perception than reality. Fundamental to this need to highlight healthspan is the idea that individuals get when they are asked if they want to live longer. Many imagine their parents or grandparents at the end of their lives when they often have major health issues and low quality of life. Then they conclude that they would not choose to live longer in that condition. This is counter to longevity research findings, which show that it is possible to intervene in late middle life and extend both healthspan and lifespan simultaneously. Emphasizing healthspan also reduces concerns of some individuals about whether it is ethical to live longer.

A drawback of this strategy exists, though: many current longevity interventions may extend healthspan more than lifespan. Lifestyle interventions such as exercise probably fit this mold. Many interventions that have dramatic health-extending effects in invertebrate models have more modest effects in mice, and there is a concern that they will be further reduced in humans. In other words, the drugs and small molecules that we are excited about today may, despite their hefty development costs and lengthy approval processes, only extend average healthspan by five or ten years and may not extend maximum lifespan at all.

Most experts in the field now acknowledge that this is a likely outcome in the near future and one focus of longevity medicine is now on achieving it. But far more is possible. Arguably, the avoidance of an emphasis on lifespan is a consequence of an overly pragmatic approach to two fundamental questions: Why do humans age and what can we do about it? These are surely two of the biggest questions in human biology. Although we try our best to ignore it, the prospect of an inevitable decline in health leading to mortality shapes our thoughts and actions. Despite the incredible advances in longevity research, these questions remain unanswered. What biological processes bring about the aged state? Can aging not just be significantly slowed, but more and more thoroughly reversed? How would humans, and their societies, be different if we achieve these goals?

It will cost billions in research and significant time to answer such questions, but we assert that it would undoubtedly pay for itself many times over. What cards need to be turned over to answer the longevity question? What interventional strategies are likely to take us beyond modest healthspan effects, and toward radical change in the rate of biological aging? Most of the lifestyle or small-molecule interventions that are currently being tested target pathways affecting longevity. These include those designed to improve metabolism, restore youthful immune function, maintain youthful body composition, eliminate deleterious cells, or improve cellular stress responses. But there are strategies on (and just over) the horizon that may have much bigger impact. These need to be seriously interrogated and resources need to be devoted to these big questions. There needs to be an acceptance and tolerance of significantly higher levels of failure in longevity research, knowing that big ideas are sometimes wrong and that the ones that are right will far outweigh the setbacks. Is radical lifespan extension foreseeable? No one can answer that question with certainty. But there are certainly enough tantalizing clues suggesting that aging is sufficiently malleable to warrant the allocation of very substantial resources.

The variation in senescent cell phenotypes creates some challenges in their elimination, as not every pathway may be shared between senescent cells, as is often observed during cancer. Furthermore, beneficial aspects of senescent cells create caveats for when and how they should be eliminated, as disruption of healing, developmental, or regenerative processes in pursuit of prevention or treatment of chronic diseases is less desirable. Thus, development of next-generation precision senolytic therapies that take advantage of potential distinctions between beneficial and detrimental senescent cells might improve safety by allowing selective clearance of those that drive the condition being treated.

Since current strategies focus on targeting pathways that promote cell survival, collateral damage to other cell types, as observed in the case of thrombocytopenia with the BCL-2 family inhibitor ABT-263, are a current target for improvement. Indeed, a modified version of ABT-263 that cannot be activated by platelets has removed one form of collateral damage, and others are currently in development.

One aspect of senescence that might be amenable to precision targeting is the temporal nature of acute vs. chronic senescence. Many beneficial aspects of senescence described thus far are transient in nature, and typically occur within a few days following induction/initiation of senescence, while chronic accumulation of senescent cells has been linked to interferon activation and age-related chronic disease. Therefore, perhaps the simplest way differentiating between beneficial and deleterious senescent cells may be by targeting effects that occur in chronic senescence and not during the more transient early response. This approach may improve outcomes in the future by improving the safety of senolytic use and more selectively only targeting those senescent cells that drive more degenerative chronic pathology.

Overall, identification of senescent cell types and their role in causing human disease will be invaluable in the creation of new senotherapeutics that might allow these contrasting phenotypes to be selectively targeted. This is a major potential benefit of the recently announced SenNet Consortium, which will map senescent cells in both murine and human tissues and help to catalog the diversity, abundance, spatial localization, and secretome of senescent cells in human and murine conditions. Beyond identification of senescent cell heterogeneity, these data will also help answer questions about translatability of findings between species, identify new biomarkers of senescence, and give indications about the origins of senescent cells across the lifespan.

Age-related hearing loss (ARHL), caused by peripheral hearing loss or central auditory processing disorder (CAPD), is the third leading cause of chronic disability in the older population. ARHL is one of the most important modifiable risk factors for dementia. Cumulative evidence links peripheral ARHL and cognitive decline with impaired performance across multiple cognitive domains, including episodic memory and processing speed. An independent association was also observed between subclinical hearing loss and cognitive impairment in a cross-sectional population study. A longitudinal cohort study further indicated that subjects with worse subclinical hearing loss have a steeper cognitive decline, as measured by the Digit Symbol Substitution Test over a mean follow-up of 9.1 years. However, a direct causal effect of peripheral hearing loss on dementia with hearing alterations is not defined. In a large cohort of cognitively healthy older people, peripheral hearing dysfunction was not associated with the pathological hallmark brain amyloid deposition of Alzheimer's disease (AD), the main phenotype of dementia. Age-related CAPD may precede the onset of clinical dementia in people with probable AD and might be an early marker of mild cognitive impairment (MCI) and AD. Older individuals with CAPD had a high risk for the subsequent onset of probable AD, and CAPD was independently associated with cognitive frailty, a frailty phenotype defined by coexisting physical frailty and MCI.

Accumulating evidence suggests that neurodegenerative pathologies add disproportionate central hearing deficits to any already existing peripheral hearing loss. Clinical findings have indicated that central auditory processing is impaired in people diagnosed with AD and its preclinical stages and may manifest many years before clinical diagnosis. Patients with semantic dementia frequently reported tinnitus and hyperacusis and were found to have abnormal neuroanatomical alterations in cortico-subcortical auditory network and limbic network. The prevalence of auditory hallucinations in Parkinson's disease and in dementia with Lewy bodies is estimated to be 8.9% and 30.8%, respectively. Neuropathological findings have indicated that AD pathological hallmarks, i.e., amyloid plaques and neurofibrillary tangles (NFTs), presented in the higher structures of the central auditory pathways and primary and secondary auditory cortical areas, but did not in the cochlea and cochlear nucleus. CAPD was persistently associated with cerebrospinal-fluid (CSF) tau levels, entorhinal and hippocampal cortex volumes, cortical thickness, and cognitive deficits in cognitively and physically healthy individuals with positive AD family history. These neuropathological alterations suggest that AD-related CAPD might not have resulted from peripheral hearing loss and induced maladaptive plastic changes.

Several hypotheses of possible etiological mechanisms have been proposed that elucidate these relationships. The common-cause hypothesis involves neurodegenerative, metabolic, and vascular pathophysiological alterations and chronic systemic inflammation during aging. The cognitive-reserve depletion or cascade hypothesis is based on brain experience-dependent neuroplasticity, cognitive reserve, and brain reserve, which refer to individual differences in the functionality and structure of the brain. The cognitive-load hypothesis proposes that individuals with hearing loss use greater cognitive resources for listening to degraded auditory signals and auditory perceptual processing, which makes these resources unavailable for other cognitive tasks, eventually leading to cognitive reserve depletion. Another hypothesis is proposed to further explain the neuropathological basis of cognitive load resulting in a vicious cycle of brain structure alterations, cognitive reserve and auditory reserve depletion. The hypothesis proposes a mechanism for the interaction between the medial temporal lobe related to auditory processing and dementia pathology, which could explain the association between hearing loss and cognitive impairment.

Microglial-related neuroinflammation affects the trajectory of Alzheimer's disease (AD), and an individual's susceptibility to AD may depend in part on the behavioral phenotype of microglia. Understanding the immune response patterns of microglia and the behavioral interaction mode of microglia with other cell types allows for the accurate targeting of microglia with impaired or abnormal responses, which has great potential for developing effective tools to delay aging and avoid neurodegenerative diseases.

In the present study, scRNA-seq analysis was performed on hippocampal samples from wide type (WT) and 5× familiar Alzheimer's disease (5× FAD) mice at 2-, 12-, and 24-month of age to map the clustering of hippocampal cells during aging and AD. We focused on the immune behavior and phenotypic characteristics of microglia. The outside and inside signal flow in the population of microglia reveals the crosstalk between neuroinflammatory pathways and cell behavior interactions guided by immune responses in the hippocampus. Our study found that blood-brain barrier (BBB) injury may increase the percentage of microglia during the progression of aging and AD.

In rodents, microglia account for 5%-12% of all central nervous system (CNS) cells and are distributed throughout the parenchyma. We found that microglia made up over 12% of the total hippocampal cells, about 45%-55% in WT mice and 45%-78% in 5× FAD mice. Maintenance of the brain microglial population is independent of circulating monocytes generated in the bone marrow and depends primarily on the self-renewal of microglia. Our scRNA-seq results showed that in WT mice, the number of microglia increased significantly at 24 months, but the fraction of microglia in the total hippocampal cells remained stable.

In the hippocampus of 5× FAD mice, the number and proportion of microglia increased abnormally at 12 months, and at 24 months, the number of microglia tended to level off compared with the 12-month of age. The accumulation of amyloid-β also showed a similar trend. This may be one of the reasons for the induction of microglial activation and proliferation. In addition, from 2 to 24 months, the PTN growth signal received by microglia in WT mice tended to decrease, suggesting that excessive growth of microglia was continuously suppressed. In 5× FAD mice, the growth and development signals were significantly enhanced at 12 months compared to those at 2 months. The uncontrolled proliferation of microglia is clearly not spontaneous but arises from environmental stimuli.

Cellular senescence is a stress-induced, permanent cell cycle arrest involved in tumor suppression and aging. Senescent cells secrete bioactive molecules such as pro-inflammatory cytokines and chemokines. This senescence-associated secretory phenotype (SASP) has been implicated in immune-mediated elimination of senescent cells and age-associated chronic inflammation. However, the mechanisms regulating the SASP are incompletely understood.

Here, we show that the stress-responsive kinase ASK1 promotes inflammation in senescence and aging. ASK1 is activated during senescence and increases the expression of pro-inflammatory cytokines and chemokines by activating p38, a kinase critical for the SASP. ASK1-deficient mice show impaired elimination of oncogene-induced senescent cells and an increased rate of tumorigenesis. Furthermore, ASK1 deficiency prevents age-associated p38 activation and inflammation and attenuates glomerulosclerosis. Our results suggest that ASK1 is a driver of the SASP and age-associated chronic inflammation and represents a potential therapeutic target for age-related diseases.

Cardiovascular diseases remain the primary cause of global mortality, necessitating effective strategies to alleviate their burden. Mitochondrial dysfunction is a driving force behind aging and chronic conditions, including heart disease. Here, we investigate the potential of Urolithin A (UA), a gut microbiome-derived postbiotic that enhances mitophagy, to ameliorate both age-related decline in cardiac function and cardiac failure.

We highlight the significance of targeting mitochondria, by comparing gene expression changes in aging human hearts and cardiomyopathies. UA oral administration successfully counteracts mitochondrial and cardiac dysfunctions in preclinical mouse models of aging and heart failure. In mice, UA improves both systolic and diastolic heart functions, distinguishing it from other mitochondrial interventions. In cardiomyocytes, UA recovers mitochondrial ultrastructural defects and decline in mitochondrial biomarkers occurring with aging and disease. These findings extend UA's benefits to heart health, making UA a promising nutritional intervention to evaluate in the clinic to promote healthy cardiovascular function as we age.

The new drug, known as SLU-PP-332, doesn't affect appetite or food intake. Nor does it cause mice to exercise more. Instead, the drug boosts a natural metabolic pathway that typically responds to exercise. In effect, the drug makes the body act like it is training for a marathon, leading to increased energy expenditure and faster metabolism of fat in the body. The drug leads obese mice to lose weight by convincing the body's muscles that they are exercising more than they really are, boosting the animals' metabolism. It also increases endurance, helping mice run nearly 50% further than they could before. All without the mice lifting a paw.

"This compound is basically telling skeletal muscle to make the same changes you see during endurance training. When you treat mice with the drug, you can see that their whole body metabolism turns to using fatty acids, which is very similar to what people use when they are fasting or exercising. And the animals start losing weight."

The new drug targets a group of proteins in the body known as estrogen-related receptors (ERRs), which are responsible for activating some of the most important metabolic pathways in energy-gobbling tissues like muscles, the heart, and the brain. The ERRs are more active when people exercise, but they have proven difficult to activate with drugs. In another paper published in March, the researchers reported that they had successfully designed SLU-PP-332 to boost activity of the ERRs. They also observed that the compound allowed normal-weight mice to run for 70% longer and 45% further than mice not receiving the drug. In their latest research, the team tested the drug on obese mice. Treating obese mice twice a day for a month caused them to gain 10 times less fat than untreated mice and lose 12% of their body weight. Yet the mice kept eating the same amount of food and didn't exercise any more.

A study sought to determine if older adults with hypertension could receive these benefits by moderately increasing their daily walking, which is one of the easiest and most popular forms of physical activity for this population. The study focused on a group of sedentary older adults between ages 68 and 78 who walked an average of about 4,000 steps per day before the study. After consulting existing studies, researchers determined that 3,000 steps would be a reasonable goal. This would also put most participants at 7,000 daily steps, in line with the American College of Sports Medicine's recommendation.

The team conducted the study during the height of the COVID-19 pandemic, which meant they had to do everything remotely. The researchers sent participants a kit with pedometers, blood pressure monitors, and step diaries for participants to log how much they were walking each day. On average, participants' systolic and diastolic blood pressure decreased by an average of seven and four points, respectively, after the intervention. Other studies suggest decreases of these magnitudes correspond to a relative risk reduction of all-cause mortality by 11%, and 16% for cardiovascular mortality, an 18% reduction in the risk of heart disease, and a 36% risk reduction of stroke.

The findings suggest that the 7,000-step regimen the participants in the study achieved is on-par with reductions seen with anti-hypertensive medications. Eight of the 21 participants were already on anti-hypertensive medications. Those participants still saw improvements in systolic blood pressure from increasing their daily activity.

Age-related hearing loss, or presbycusis, is a common cause of hearing loss in elderly people worldwide. It typically presents as progressive, irreversible, and usually affects the high frequencies of hearing, with a tremendous impact on the quality of life. Presbycusis is a complex multidimensional disorder, in addition to aging, multiple factors including exposure to noise, or ototoxic agents, genetic susceptibility, metabolic diseases, and lifestyle can influence the onset and severity of presbycusis.

With the aging of the body, its ability to clean up deleterious substances produced in the metabolic process is weakened, and the self-protection and repair function of the body is reduced, which in turn leads to irreversible damage to the cochlear tissue, resulting in the occurrence of presbycusis. Presently, oxidative stress (OS), mitochondrial DNA damage, low-grade inflammation, decreased immune function, and stem cell depletion have been demonstrated to play a critical role in developing presbycusis. The purpose of this review is to illuminate the various mechanisms underlying this age-related hearing loss, with the goal of advancing our understanding, prevention, and treatment of presbycusis.

To elucidate the relationship between aging and cognitive decline, it is important to understand the structural changes in the brain that occur throughout aging as a potential mechanistic explanation. One example of structural changes that are typically associated with older age is the presence of white matter hyperintensities (WMHs). WMHs are a neuroimaging marker of small vessel disease and are often indicative of chronic, insufficient cerebrovascular supply.

The accrual of WMHs is a subtle, progressive process typically associated with cardiovascular risk factors (e.g., body mass index, hypertension, or diabetes) and aging. There is also evidence that both age and cardiovascular risk factors predict increasing WMH load over time. This is supported by findings suggesting that increasing physical activity or controlling vascular risk factors such as blood pressure can slow the progression of WMHs.

We aimed to investigate if WMH load is a mediator of the relationship between age and cognitive decline. Healthy participants (N = 166, 20-80 years) completed the Montreal Cognitive Assessment (MoCA). WMHs were manually delineated on fluid-attenuated inversion recovery (FLAIR) scans. Mediation analysis was conducted to determine if WMH load mediates the relationship between age and cognition. Older age was associated with worse cognition, but this was an indirect effect: older participants had more WMHs, and, in turn, increased WMH load was associated with worse MoCA scores. Thus WMH load mediates the relationship between age and cognitive decline. Importantly, this relationship was not moderated by age, i.e., increased WMH severity is associated with poorer MoCA scores irrespective of age.

Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation, chromatin reconfiguration and exit from the cell cycle, instating a barrier for adult heart regeneration. Here, to explore whether metabolic reprogramming can overcome this barrier and enable heart regeneration, we abrogate fatty acid oxidation in cardiomyocytes by inactivation of Cpt1b. We find that disablement of fatty acid oxidation in cardiomyocytes improves resistance to hypoxia and stimulates cardiomyocyte proliferation, allowing heart regeneration after ischaemia-reperfusion injury.

Metabolic studies reveal profound changes in energy metabolism and accumulation of α-ketoglutarate in Cpt1b-mutant cardiomyocytes, leading to activation of the α-ketoglutarate-dependent lysine demethylase KDM5. Activated KDM5 demethylates broad H3K4me3 domains in genes that drive cardiomyocyte maturation, lowering their transcription levels and shifting cardiomyocytes into a less mature state, thereby promoting proliferation. We conclude that metabolic maturation shapes the epigenetic landscape of cardiomyocytes, creating a roadblock for further cell divisions. Reversal of this process allows repair of damaged hearts.

Microglia are immune cells in the brain responsible for clearing beta-amyloid plaques. As Alzheimer's disease progresses, microglia can lose their capacity to remove these plaques and instead produce inflammatory mediators that may accelerate beta-amyloid plaque progression. Researchers have found that accumulating another subtype of immune cells, called CD8+ T cells, is essential to slow this process by interacting with microglia. This interaction, in turn, was important to limit beta-amyloid burden and preserve memory capabilities in a mouse model of the disease.

To understand how T cells were delaying symptom progression in their Alzheimer's disease model, researchers searched for the most abundant molecular interaction between CD8+ T cells and the microglia. They found a protein on the surface of CD8+ T cells, CXCR6, interacts with the protein CXCL16 expressed by microglia. The two surface proteins, CXCR6 and CXCL16, essentially performed a handshake between the two cells, communicating in both directions. Just like the firmness of a human handshake can convey information, so can the interaction of these two proteins on the outside of their respective cells.

The scientists determined how the handshake occurs and delays the onset of Alzheimer's disease-related pathologies. The CD8+ T cells first move next to the microglia, which are localized next to the beta-amyloid plaques. Then, the CD8+ T cells use the handshake to signal to the microglia to stop causing uncontrolled inflammation, which, in turn, slows plaque growth and symptoms in the mouse models. When the scientists deleted the gene for the CD8+ T cell's protein CXCR6, the mice developed worse Alzheimer's disease-related symptoms. This effect was partially because the CD8+ T cells without CXCR6 failed to accumulate in the brain near the microglia or plaque site. These cells also did not acquire the appropriate suppressive function. Thus, disrupting the CD8+ T cell's ability to perform the handshake prevented its protective effect against Alzheimer's disease symptoms.

mTORC1 (mechanistic target of rapamycin complex 1) is a metabolic sensor that promotes growth when nutrients are abundant. Ubiquitous inhibition of mTORC1 extends lifespan in multiple organisms but also disrupts several anabolic processes resulting in stunted growth, slowed development, reduced fertility, and disrupted metabolism. However, it is unclear if these pleiotropic effects of mTORC1 inhibition can be uncoupled from longevity. Here, we utilize the auxin-inducible degradation (AID) system to restrict mTORC1 inhibition to C. elegans neurons. We find that neuron-specific degradation of RAGA-1, an upstream activator of mTORC1, or LET-363, the ortholog of mammalian mTOR, is sufficient to extend lifespan in C. elegans.

Unlike raga-1 loss of function genetic mutations or somatic AID of RAGA-1, neuronal AID of RAGA-1 robustly extends lifespan without impairing body size, developmental rate, brood size, or neuronal function. Moreover, while degradation of RAGA-1 in all somatic tissues alters the expression of thousands of genes, demonstrating the widespread effects of mTORC1 inhibition, degradation of RAGA-1 in neurons only results in around 200 differentially expressed genes with a specific enrichment in metabolism and stress response. Notably, our work demonstrates that targeting mTORC1 specifically in the nervous system in C. elegans uncouples longevity from growth and reproductive impairments, and that many canonical effects of low mTORC1 activity are not required to promote healthy aging. This data challenges previously held ideas about the mechanisms of mTORC1 lifespan extension and underscore the potential of promoting longevity by neuron-specific mTORC1 modulation.

Studies have shown that even before Alzheimer's symptoms appear, brain activity is disrupted in people who go on to develop the disease. There is neuronal hyperactivity and signal disorganization in the brain. The main inhibitor of neuronal signals in the human brain is the neurotransmitter GABA. It works in close collaboration with a cotransporter, KCC2. This is an ion pump, located in the cell membrane, which circulates chloride and potassium ions between the inside and outside of neurons. "A loss of KCC2 in the cell membrane can lead to neuronal hyperactivity. One study has already shown that KCC2 levels were reduced in the brains of deceased Alzheimer's patients. This gave us the idea of examining the role of KCC2 in an animal model of Alzheimer's disease."

Scientists used mice expressing a manifestation of Alzheimer's disease. The researchers found that when these mice reached the age of four months, KCC2 levels decreased in two regions of their brains: the hippocampus and the prefrontal cortex. These two regions are also affected in people suffering from Alzheimer's disease. In light of these results, the researchers turned to a molecule developed in their laboratory, CLP290, a KCC2 activator that prevents its depletion. In the short term, the administration of this molecule to mice that already had reduced KCC2 levels improved their spatial memory and social behaviour. In the long term, CLP290 protected them against cognitive decline and neuronal hyperactivity. "Our results do not imply that the loss of KCC2 causes Alzheimer's disease. On the other hand, it does appear to cause an ionic imbalance leading to neuronal hyperactivity that can lead to neuronal death. This suggests that by preventing the loss of KCC2, we could slow down and perhaps even reverse certain manifestations of the disease."