Fight Aging! Newsletter, December 28th 2020

Based on neuropathological similarities of glaucoma with other age-related neurodegenerative diseases such as Alzheimer's and the involvement of the ubiquitin-proteasome and chaperone systems, researchers have hypothesized a cellular senescence contribution to glaucoma pathogenesis. Preclinical evidence has supported the cellular senescence hypothesis as a contributor to glaucoma pathogenesis. Senescent cells secrete a plethora of molecules known as senescence associated secretory proteins (SASP), which affect surrounding cells by inducing either apoptosis or senescence, thus propagating the phenotype. There are several senolytic drugs that are able to specifically target senescent cells to overcome the apoptosis block to remove them, presenting an attractive hypothesis for potential treatment of glaucoma.

Indeed, our recent study has shown that targeting senescent retinal ganglion cells (RGCs) in a mouse model of glaucoma using the senolytic drug dasatinib protected the remaining RGCs and visual function from glaucomatous injury. These data are also supported by evidence from human studies, as a bioinformatics analysis of genes associated with primary open angle glaucoma suggested senescence as a key factor in pathogenesis.

Little is known about the neuroprotective effects or safety of senolytic drugs on vision in human patients, however. Clinical management of glaucoma involves acquisition of extensive longitudinal data including visual acuity, intraocular pressure (IOP), visual field sensitivity, and retinal nerve fiber thickness. Compared to other neurodegenerative diseases that often lack objective standardized metrics of clinical progression, some of these ophthalmic data are readily available and amenable to investigations of novel therapeutics, including senolytic drugs. To this end, we performed a retrospective analysis of existing clinical data to evaluate the effect of senolytics on vision and glaucoma progression. For the current study, we queried the electronic health record (EHR) system of a large academic medical center to identify glaucoma and glaucoma suspect patients exposed to at least one senolytic drug and conducted several analyses of visual data.

Senolytic exposure was not associated with decreased visual acuity, elevated intraocular pressure, or documentation of senolytic-related adverse ocular effects by treating ophthalmologists. Additionally, patients exposed to senolytics (n = 9) did not exhibit faster progression of glaucomatous visual field damage compared to matched glaucoma patients (n = 26) without senolytic exposure. These results suggest that senolytic drugs do not carry significant ocular toxicity and provide further support for additional evaluation of the potential neuroprotective effects of senolytics on glaucoma and other neurodegenerative diseases.

Mitochondria are the power plants of our cells. They are essential for converting the energy in the food we eat into the common energy currency that is required for a variety of cellular functions. Cancer cells are critically dependent on mitochondria, not only for providing energy but also for producing a variety of building blocks needed to make more cells as the cancer cells divide. The continuous cell division means that a cancer cell must constantly make new mitochondria in order to grow.

Previous attempts to target mitochondria for cancer treatment have focused on acutely inhibiting mitochondrial function. However, this strategy has often resulted in severe side effects due to the crucial role of mitochondria for normal tissue function. As an alternative, researchers developed a novel strategy that does not directly interfere with the function of existing mitochondria. Instead, they designed highly selective inhibitors that target the mitochondria's own genetic material, mtDNA, which has a critical role in the formation of new mitochondria.

When investigating the mechanism of action of these novel inhibitors, the researchers observed that the inhibitors put cancer cells into a state of severe energy and nutrient depletion. This leads to loss of necessary cellular building blocks, reduced tumour cell growth and ultimately cell death. "Previous findings from our research group have shown that rapidly dividing cells, such as cancer cells, are crucially dependent on mtDNA to form new functional mitochondria. Consequently, treatment with our inhibitors specifically affects proliferation of tumour cells, whereas healthy cells in tissues such as skeletal muscle, liver, or heart remain unaffected for a surprisingly long time."

Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration, and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system. The IMTs efficiently impair mtDNA transcription and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines.

The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease.

A helpful approach to put the effects of the pandemic in context is to compare COVID-19-related mortality rates with the leading causes of death that, under ordinary circumstances, would pose the greatest threat to different age groups. The conditions listed in the table include the three leading causes of death in each of the 10 age groups from infancy to old age. Using data from the Centers for Disease Control and Prevention, the table shows mortality rates for these conditions during the period of March through October 2018 (the most recent year for which detailed cause-of-death data are available) with COVID-19 mortality rates during March through October 2020.

The table shows that by October 2020 COVID-19 had become the third leading cause of death for persons aged 45 through 84 years and the second leading cause of death for those aged 85 years or older. Adults 45 years or older were more likely to die from COVID-19 during those months than from chronic lower respiratory disease, transport accidents (eg, motor vehicle fatalities), drug overdoses, suicide, or homicide. In contrast, for individuals younger than age 45 years, other causes of death, such as drug overdoses, suicide, transport accidents, cancer, and homicide exceeded those from COVID-19.

Between November 1, 2020, and December 13, 2020, the 7-day moving average for daily COVID-19 deaths tripled, from 826 to 2430 deaths per day, and if this trend is unabated will soon surpass the daily rate observed at the height of the spring surge (2856 deaths per day on April 21, 2020). As occurred in the spring, COVID-19 has become the leading cause of death in the United States (daily mortality rates for heart disease and cancer, which for decades have been the two leading causes of death, are approximately 1700 and 1600 deaths per day, respectively). With COVID-19 mortality rates now exceeding these thresholds, this infectious disease has become deadlier than heart disease and cancer, and its lethality may increase further as transmission increases with holiday travel and gatherings and with the intensified indoor exposure that winter brings.

How did your group first get interested in the idea of plasma dilution? I understand that Irina Conboy's work had a certain influence?

Not just influence. It played a central role. The Conboys' study was published in May. It showed that simple plasma dilution can recapitulate most of the benefits of parabiosis. The original parabiosis results hinted on the existence of certain systemic factors of aging and at the possibility of its reversal. This recent study made the procedure easier and eliminated ethical controversies. The procedure is almost similar to donating blood plasma. This simple procedure yielded some interesting results: it triggered muscle regeneration in mice, liver regeneration in older animals, and improved neurogenesis. Recently, in late November, I think, another study was published that showed some real cognitive improvement following this procedure. So, now we have some serious proof that blood contains signaling molecules that harm the organism, but there is no data on whether this procedure actually prolongs lifespan. I think there is a reason for it. It is highly unlikely that this procedure results in any meaningful life extension. I think most of the effect is on healthspan rather than on lifespan. It is still good news, since we currently have very few ways to extend healthspan.

Why did you decide to participate in this small-scale experiment on humans?

Our team has existed for some time now. It is a small community of biohackers. It seemed like a great way to quickly test this intervention, get some results fast, and tell people about it.

How did you choose the tests for the panel?

It would have been interesting to look at cognitive and muscular markers, but both our participants were too young: 50-60 years old. They probably do not have sarcopenia or cognitive decline yet, so there was no way for us to measure it. We chose different biomarkers, such as liver function - both of our participants had had some abnormalities in their liver biomarkers. We wanted to check kidney function because it declines with age. We checked the immune system, because as we age, the number of naïve T cells declines, and these are indispensable for fighting new infections. Hematopoietic cell aging is characterized by a shift towards myeloid progenitors. We looked at the ratio of neutrophils and lymphocytes, how it changed. Cholesterol is another important marker in the lipid profile of blood. We did a very comprehensive lipid profile that included a rare biomarker that many labs do not check for - oxidized low-density lipoproteins (Ox-LDL). I can say that this marker plummeted all the way down to its normal level in one participant that had it elevated prior to the procedure. We also checked for various hormones, including insulin-like growth factor (IGF), that are related to aging and lifespan, and many other markers, including biochemical ones, such as urea and uric acid, along with oxidative stress markers, such as lipid peroxidation products and glutathione. Contrary to epigenetic clocks, these markers can be clinically interpreted.

Do you plan to publish the results, maybe as a case study?

We have all the data published on our website so that researchers can see it. We do not plan to publish an article. First, I am convinced that soon we will have full-scale clinical trials of this method, maybe by the Conboys, and there is something in the works here in Russia as well. I do not know how valuable our data is, considering our sample size was just two people. We just wanted to see whether it was possible to arrange such an intervention in humans using the means we had at our disposal, and whether it would do any good. Now we know it actually did some good, in terms of the number of naïve T-cells, levels of oxidized LDL. The drop in Ox-LDL levels was probably due not simply to dilution but to some deeper processes, because in one participant, these levels declined, while in the other they went up from an originally low level. So, in both participants, LDL levels normalized and stayed normal for at least two weeks. Liver markers improved by a lot, and the myelocyte/lymphocyte ratio improved. There were some controversial results, such as one participant having insulin levels decline four-fold but not the other one.

Aging is a complex process that can be characterized by functional and cognitive decline in an individual. Aging can be assessed based on the functional capacity of vital organs and their intricate interactions with one another. Thus, the nature of aging can be described by focusing on a specific organ and an individual itself. However, to fully understand the complexity of aging, one must investigate not only a single tissue or biological process but also its complex interplay and interdependencies with other biological processes.

Here, using RNA-seq, we monitored changes in the transcriptome during aging in four tissues (including brain, blood, skin and liver) in mice at 9 months, 15 months, and 24 months, with a final evaluation at the very old age of 30 months. We identified several genes and processes that were differentially regulated during aging in both tissue-dependent and tissue-independent manners. Most importantly, we found that the electron transport chain (ETC) of mitochondria was similarly affected at the transcriptome level in the four tissues during the aging process. We also identified the liver as the tissue showing the largest variety of differentially expressed genes (DEGs) over time. Lcn2 (Lipocalin-2) was found to be similarly regulated among all tissues, and its effect on longevity and survival was validated using its orthologue in Caenorhabditis elegans.

In conclusion, our study demonstrated that the molecular processes of aging are relatively subtle in their progress, and the aging process of every tissue depends on the tissue's specialized function and environment. Hence, individual gene or process alone cannot be described as the key of aging in the whole organism.

A large part of metabolomics research relies on experiments involving mouse models, which are usually 6 to 20 weeks of age. However, in this age range mice undergo dramatic developmental changes. Even small age differences may lead to different metabolomes, which in turn could increase inter-sample variability and impair the reproducibility and comparability of metabolomics results. In order to learn more about the variability of the murine plasma metabolome, we analyzed male and female C57BL/6J, C57BL/6NTac, 129S1/SvImJ, and C3HeB/FeJ mice at 6, 10, 14, and 20 weeks of age, using targeted metabolomics.

Our analysis revealed high variability of the murine plasma metabolome during adolescence and early adulthood. A general age range with minimal variability, and thus a stable metabolome, could not be identified. Age-related metabolomic changes as well as the metabolite profiles at specific ages differed markedly between mouse strains. This observation illustrates the fact that the developmental timing in mice is strain specific. We therefore stress the importance of deliberate strain choice, as well as consistency and precise documentation of animal age, in metabolomics studies.

High blood pressure appears to accelerate a decline in cognitive performance in middle-aged and older adults. Nearly half of American adults have high blood pressure or hypertension. Having high blood pressure is a risk factor for cognitive decline, which includes such things as memory, verbal fluency, attention and concentration. Blood pressure of 120 mmHg - 129 mmHg systolic (the top number in a reading) or higher is considered elevated. Systolic pressure above 130 mmHg, or diastolic pressure (the bottom number) of 80 mmHg or higher is considered hypertension.

Researchers analyzed findings from an existing study that included blood pressure and cognitive health information for more than 7,000 adults in Brazil, whose average age was about 59 years old at the study's start. The study participants were followed for an average of nearly 4 years; testing included analysis of memory, verbal fluency, and executive function, which includes attention, concentration, and other factors associated with thinking and reasoning.

Systolic blood pressure between 121 and 139 mmHg or diastolic blood pressure between 81 and 89 mmHg with no antihypertensive medication use was associated with accelerated cognitive performance decline among middle-aged and older individuals. The speed of decline in cognition happened regardless of hypertension duration, meaning high blood pressure for any length of time, even a short duration, might impact a person's speed of cognitive decline. Adults with uncontrolled hypertension tended to experience notably faster declines in memory and global cognitive function than adults who had controlled hypertension.

"In addition to other proven benefits of blood pressure control, our results highlight the importance of diagnosing and controlling hypertension in patients of any age to prevent or slow down cognitive decline. Our results also reinforce the need to maintain lower blood pressure levels throughout life, since even prehypertension levels were associated with cognitive decline."

Caloric restriction (CR) has been shown repeatedly to prolong the lifespan in laboratory animals, with its benefits dependent on molecular targets forming part of the nutrient signaling network, including the NAD-dependent deacetylase silent mating type information regulation 2 homologue 1 (SIRT1). It has been hypothesized that the stilbene resveratrol (RSV) may counteract age- and obesity-related diseases similarly to CR. In yeast and worms, RSV-promoted longevity also depended on SIRT1.

While it remains unclear whether RSV can prolong lifespans in mammals, some studies in rodents supplemented with RSV have reported lowered body weight (BW) and fat mass, improved insulin sensitivity, lowered cholesterol levels, increased fitness, and mitochondrial biogenesis. Molecular mechanisms possibly leading to such changes include altered gene transcription and activation of SIRT1, AMP-activated kinase (AMPK), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A). However, some mouse models did not benefit from RSV treatment to the same extent as others.

We conducted a literature search for trials directly comparing RSV application to CR feeding in mice. In most studies retrieved by this systematic search, mice supplemented with RSV did not show significant reductions of BW, glucose, or insulin. Moreover, in some of these studies, RSV and CR treatments affected molecular targets differently and/or findings on RSV and CR impacts varied between trials. Although there may be a moderate effect of RSV supplementation on parameters such as insulin sensitivity toward a more CR-like profile in mice, data are inconsistent. Likewise, RSV supplementation trials in humans report controversial findings. While we consider that RSV may, under certain circumstances, moderately mimic some aspects of CR, current evidence does not fully support its use to prevent or treat age- or obesity-related diseases.

Very few studies have explored the patterns of cardiovascular health (CVH) metrics in midlife and late life in relation to risk of dementia. We examined the associations of composite CVH metrics from midlife to late life with risk of incident dementia. This cohort study included 1,449 participants from the Finnish Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study, who were followed from midlife (baseline from 1972 to 1987; mean age 50.4 years; 62.1% female) to late life (1998), and then 744 dementia-free survivors were followed further into late life (2005 to 2008). We defined and scored global CVH metrics based on 6 of the 7 components (i.e., smoking, physical activity, and body mass index [BMI] as behavioral CVH metrics; fasting plasma glucose, total cholesterol, and blood pressure as biological CVH metrics) following the modified American Heart Association (AHA)'s recommendations. Then, the composite global, behavioral, and biological CVH metrics were categorized into poor, intermediate, and ideal levels. Dementia was diagnosed following the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria.

During the follow-up examinations, dementia was diagnosed in 61 persons in 1998 and additional 47 persons in 2005 to 2008. The fully adjusted hazard ratio (HR) of dementia was 0.71 and 0.52 for midlife intermediate and ideal levels (versus poor level) of global CVH metrics, respectively; the corresponding figures for late-life global CVH metrics were 0.60 and 0.91 . Compared with poor global CVH metrics in both midlife and late life, the fully adjusted HR of dementia was 0.25 for people with intermediate global CVH metrics in both midlife and late life and 0.14 for those with midlife ideal and late-life intermediate global CVH metrics. Having an intermediate or ideal level of behavioral CVH in both midlife and late life (versus poor level in both midlife and late life) was significantly associated with a lower dementia risk, whereas people with midlife intermediate and late-life ideal biological CVH metrics had a significantly increased risk of dementia.

In this study, we observed that having the ideal CVH metrics, and ideal behavioral CVH metrics in particular, from midlife onwards is associated with a reduced risk of dementia as compared with people having poor CVH metrics. Maintaining life-long health behaviors may be crucial to reduce late-life risk of dementia.

Unity Biotechnology is way ahead of the pack: No other company is in the clinic (though Mayo Clinic has a Dasatinib + Quercetin Phase 2 trial). Unity has already completed a Phase 2 (UBX0101, failed) and they are currently conducting a new Phase 1 (UBX1325). But first is not always best - Unity's approach is somewhat crude compared to the targeted approaches of newer senolytics companies. But perhaps it will be enough. More senolytic trials are coming: Unity won't be alone in the clinical stage for long. I believe that FoxBio, Senolytic Therapeutics, Numeric Biotech, and Rubedo Life Science will be in the clinic within 12 - 24 months.

1st Gen vs 2nd Gen: Dasatinib, Navitoclax, UBX0101 were 1st generation senolytics developed by hypothesis: That existing drugs that targeted anti-apoptotic pathways might also clear senescent cells. Unfortunately, many of these 1st gen drugs have off-target effects that kill non-senescent cells, too. Now it appears the majority of the industry is focusing on 2nd generation therapies through high-throughput screens to improve selectivity. Novel targeted modalities (peptides, monoclonal antibodies, gene therapy, immunotherapy, RNA) and delivery (nanoparticles and conjugate prodrugs) are being developed as well.

Unity Biotechnology is the only senolytics company to go public so far. However, Juvenescence is planning to go public within ~6 months, at which point you will be able to own a slice of FoxBio. The current market is amenable to IPOs so I wouldn't be surprised if another senolytics company went public just before their Phase 1 trials - perhaps in the next two to three years, should markets hold up.

The majority of companies are focussing on killing senescent cells with senolytics. However, four companies have senomorphic pipelines (Senolytic Therapeutics, Senisca, Atropos Therapeutics, Dorian Therapeutics). I'm excited to see which approach will prove most effective, though I am less sanguine on the clinical prospects of approaches that merely slow senescence.

Would a second Unity Biotechnology failure have an impact on the future of senolytics? Yes and no. Unity is just one of many companies developing senolytics and their current clinical trials are only testing the earliest senolytic strategy (1st gen). There are many more senolytics companies aiming for clinical trials in the next two years and some will be testing 2nd generation targeted therapies. If UBX1325 were to fail in Phase 2 the immediate effect would be a decrease in unsophisticated capital in the senolytics space - from those who don't understand the other promising targets and modalities in development. This might be a notable amount of money in the short term but long term I am optimistic about senolytics. All it takes is one success for the floodgates to open.

Adipose tissue is not just a simple reservoir of energy for periods of food scarcity. It contributes significantly to regulation of the metabolism, releasing various molecules into the bloodstream, including microRNAs that modulate the expression of key genes in different parts of the organism, including the liver, pancreas, and muscles. Research has shown that both aging and obesity can impair the production of these regulatory microRNAs by adipose tissue and favor the development of diseases such as diabetes and dyslipidemia.

Results showed the occurrence of communication between muscle and adipose tissue during aerobic exercise via signaling molecules secreted into the bloodstream. This exchange of information makes energy consumption by adipose cells more efficient, enabling the metabolism to adapt to exercise and enhancing the performance of the muscles. Mice were subjected to a 60-minute treadmill running protocol for eight weeks. As they became fitter, treadmill speed and inclination were increased. At the end, in addition to the improvement in performance, the scientists found a significant elevation in adipocyte levels of DICER expression, which was accompanied by a reduction in body weight and visceral fat.

When they repeated the experiment with mice that were genetically modified not to express DICER in adipose cells, the researchers found that the beneficial effects of aerobic exercise were far smaller. "The animals didn't lose weight or visceral fat, and their overall fitness didn't improve. We also observed that adipose cells used the energy substrate differently in these GM mice than in wild mice, leaving less glucose available for muscles." In humans, six weeks of high-intensity interval training (HIIT) were sufficient to yield a fivefold increase in the amount of DICER in adipose tissue on average. The effect was observed in both younger volunteers, aged about 36, and older subjects, aged about 63. The response varied considerably between individuals, however, with DICER increasing as much as 25 times in some, and very little in others.

"We identified a molecule called miR-203-3p, whose expression increases with both training and caloric restriction. We showed that this microRNA is responsible for promoting metabolic adjustment in adipocytes. When muscles use up all their glycogen during prolonged exercise, molecular signals are sent to adipose tissue and miR-203-3p fine-tunes the adipocyte metabolism. We found this metabolic flexibility to be essential to good health as well as performance enhancement. In genetically modified mice that don't express DICER in adipocytes, this conversation between adipose tissue and muscles doesn't happen. It's a model that mimics aging and obesity. So when DICER declines, metabolic health is poor and degenerative processes accelerate."

While more attention has been placed on mitochondrial electron leak and consequent free radical generation, proton leak is a highly significant aspect of mitochondrial energetics, as it accounts for more than 20% of oxygen consumption in the liver and 35-50% of that in muscle in the resting state. There are two types of proton leak in the mitochondria: (1) constitutive, basal proton leak, and (2) inducible, regulated proton leak, including that mediated by uncoupling proteins (UCPs). In skeletal muscle, a majority of basal proton conductance has been attributed to adenine nucleotide translocase (ANT). Although aging-related increased mitochondrial proton leak was detected in the mouse heart, kidneys, and liver by indirect measurement of oxygen consumption in isolated mitochondria, direct evidence of functional impact remains to be further investigated. Moreover, the exact site and underlying mechanisms responsible for aging-related mitochondrial proton leak are unclear.

SS-31 (elamipretide) binds to cardiolipin-containing membranes and improves cristae curvature. Prevention of cytochrome c peroxidase activity and release has been proposed as its major basis of activity. SS-31 is highly effective in increasing resistance to a broad range of diseases, including heart ischemia reperfusion injury, heart failure, neurodegenerative disease, and metabolic syndrome. In aged mice, SS-31 ameliorates kidney glomerulopathy and brain oxidative stress and has shown beneficial effects on skeletal muscle performance. We have recently shown that administration of SS-31 to 24-month-old mice for 8 weeks reverses the age-related decline in diastolic function, restoring this parameter 35% toward that of young (5-month-old) mice. However, how SS-31 benefits and protects aged cardiac cells remains unclear.

In this report, we investigated the effect and underlying mechanism of action of SS-31 on aged cardiomyocytes, especially on the mitochondrial proton leak. Using the naturally aged rodent model we provided direct evidence of increased proton leak as the primary energetic change in aged mitochondria. We further show that the inner membrane protein ANT1 mediates the augmented proton entry in the old mitochondria. Most significantly, we demonstrate that SS-31 acutely prevents the excessive mitochondrial proton entry and rejuvenates mitochondrial function through direct association with ANT1 and stabilization of the ATP synthasome.

Age-related hearing loss (ARHL), or presbycusis, is a progressive and pathological process that results from age-related degeneration of the cochlea and central auditory system. It affects almost half of individuals over the age of 75 years. It is characterized by significant elevations in the hearing threshold with reductions in speech discrimination and difficulty in localization of sound sources, particularly in noisy environments. Previous studies have shown that the loss of outer hair cells (OHCs), damage to the stereocilia, and degenerated alterations of the auditory nerves are possible mechanisms underlying ARHL. However, recent studies have reported that these degenerative morphological changes in the cochlea occur after the onset of the hearing disorder. For example, specific noise exposure can cause hearing loss coupled with intact cochlear hair cells, stereocilia, and spiral ganglion neurons (SGNs), which suggests that other cochlear components may be responsible for hearing loss.

Both the ototoxic drugs such as gentamicin, and noise exposure have been proposed to cause a loss of ribbon synapses, which account for hearing impairment. Ribbon synapses of the inner hair cells (IHCs) are formed on the cochlea with a powerful function specialized for encoding acoustic signals with high temporal precision over long periods. It has been reported that aging cochlea could form unexpected folded endings in the postsynaptic nerve terminals, suggesting that aging could affect the morphologies or function of ribbon synapses. However, it remains unclear whether the quantity and function of the ribbon synapse are initially disrupted and thus contribute to the consequent hearing loss during aging.

In this study, we aimed to verify whether cochlear ribbon synapses are vulnerable to aging insult in C57BL/6J mice, a widespread model for ARHL. We explored the correlation between the number and function of ribbon synapses and the reduction of hearing function in the early stage of aging. We found that the loss of cochlear ribbon synapses is an initial pathological event in the early stage of aging, which causes hearing loss and may consequently induce loss or damage to other cochlear components, such as IHCs, and SGNs.

The benefits of discovering therapeutics that target aging are many, including (1) decreasing the financial burden on our strained healthcare system, (2) increasing the amount of time older adults live free of chronic diseases (often denoted as healthspan), and (3) potentially increasing maximum human lifespan. Organismal lifespan was first presented as a genetically modifiable trait by groundbreaking publications describing the effects of the FOXO transcription factor DAF-16 on longevity in Caenorhabditis elegans. Although modifying genes or substantially changing environments is not plausible in humans, it is feasible to find anti-aging therapeutics that mimic environmental cues or genetic signaling environments.

Deciphering how cells relay information to one another remains one of the foundational discoveries in biology. This concept, that cells can relay critical information to other cells in response to an initial signaling cue, allows for genes expressed in one cell or tissue to affect the physiology of other cells and tissues. This ability of genes to affect processes outside of the cells they are expressed in is often referred to as cell non-autonomous action or signaling.

More recently, high-profile publications from multiple labs have shown that many signaling pathways reported to improve longevity (e.g. mitochondrial stress, insulin-like signaling, heat shock, and the hypoxic response) act through cell non-autonomous signaling mechanisms. These pathways originate in sensory cells, often neurons, that signal to peripheral tissues and promote survival during the presence of stress. Importantly, this activation of stress response pathways, either through genetic modification or exposure to environmental stress, is often sufficient to improve health and longevity. Additionally, genetic modification of these pathways can often target the aging process while sparing growth/development/reproduction effects that are often consequences of environmental stress. Understanding how cell non-autonomous signaling influences longevity is a relatively recent concept in aging research and presents a novel opportunity to discover pharmacological interventions that modulate signaling to increase healthspan and longevity.

With the establishment of cell non-autonomous regulation of aging in multiple pathways and organisms, there is immense therapeutic potential for this area going forward. Most therapeutics logically target the tissues where physiological change is important, while understanding signaling networks provides a unique opportunity to use the natural signaling network to 'trick' key tissues into improving long-term health. This will not necessarily be easy, as targeting neural circuits using broad drugs (e.g. SSRIs) often have pleiotropic effects, but the better we understand the signaling networks the more specifically we could, in theory, mimic the signals. Using a signaling approach to anti-aging therapeutics would allow for induction of hormetic effects without the need for an acute stress, and has great potential to mimic well-established longevity interventions such as dietary restriction.

Researchers have developed a novel type of nanoparticle that efficiently and selectively kills cancer cells, thus opening up new therapeutic options for the treatment of tumors. Both calcium phosphate and citrate are involved in the regulation of many cellular signaling pathways. Hence, the levels of these substances present in the cytoplasm are tightly controlled, in order to avoid disruption of these pathways. Crucially, the nanoparticles described in the new study are able to bypass these regulatory controls. Researchers repared amorphous and porous nanoparticles consisting of calcium phosphate and citrate, which are encapsulated in a lipid layer. The encapsulation ensures that these particles are readily taken up by cells without triggering countermeasures. Once inside the cell, the lipid layer is efficiently broken down, and large amounts of calcium and citrate are deposited in the cytoplasm.

Experiments on cultured cells revealed that the particles are selectively lethal - killing cancer cells, but leaving healthy cells (which also take up particles) essentially unscathed. During cellular uptake, the nanoparticles acquire a second membrane coat. The authors of the study postulate that an unknown mechanism - which is specific to cancer cells - causes a rupture of this outer membrane, allowing the contents of the vesicles to leak into the cytoplasm. In healthy cells, on the other hand, this outermost layer retains its integrity, and the vesicles are subsequently excreted intact into the extracellular medium.

"The highly selective toxicity of the particles made it possible for us to successfully treat two different types of highly aggressive pleural tumors in mice. With only two doses, administered locally, we were able to reduce tumor sizes by 40 and 70%, respectively. Furthermore, over the course of a 2-month treatment, no signs of serious side-effects were detected."

Researchers know that mitochondria play an important role in aging. Specifically, when mitochondria are harmed in some way and their function is impaired, a process called mitochondrial unfolded protein response (UPRmt) occurs that repairs mitochondria and benefits cell survival. Therefore, some scientists think it is possible to increase lifespan by identifying drugs that activate UPRmt. A team of scientists searched through a chemical library of existing drugs to find one that can activate this stress response in the worm Caenorhabditis elegans. They found that an anti-hypertension drug called metolazone prolongs C. elegans lifespan, marking the first step in developing anti-aging pharmaceuticals.

Past experiments with Caenorhabditis elegans - a worm commonly used in biological research as a model - have found several compounds that increase the worm's lifespan by triggering UPRmt. Against the backdrop of these previous studies, this team screened about 3,000 drugs in worms that are engineered to glow if drug treatment activates hsp-6, a gene that is highly expressed when UPRmt occurs. It is interesting to note that of these 3000 drugs, 1300 were off-patent drugs approved by regulatory agencies, and the remaining 1700 were unapproved bioactive ones.

Through this method, the team identified metolazone, a drug used to treat heart failure and high blood pressure. They then tested the drug on C. elegans and found that it increased wild-type worm lifespan. Additionally, they found that metolazone did not extend lifespans in worms in whom the genes atfs-1, ubl-5, and nkcc-1 were mutated and thus non-functional. The former two genes are known to be essential for UPRmt function, suggesting that metolazone is acting on the UPRmt pathway. The third gene, nkcc-1, encodes a protein that is part of a protein family targeted by metolazone in its usual function as an anti-hypertension drug. The fact that metolazone did not increase the lifespans of nkcc-1 mutated C. elegans suggests that the drug may need to block the nkcc-1 protein to activate the UPRmt pathway.