We finally are beginning to understand the biological basis of aging and age-related diseases, making the discovery of new therapies actionable for the first time. Aging and its underlying biological mechanisms are becoming recognized as a catalyst, if not the central catalyst, for a wide range of poorly treated prevalent diseases. This is a promising new area in science providing actionable insights with potential for tremendous impact on human healthspan.

I have been following the field of the biology of aging since the beginning of my career in science, more than thirty years, while working in targeted ways to find and advance new therapies in the areas of metabolic and cardiovascular disease. Recently, I became the CEO of a biotechnology company, Navitor Pharmaceuticals, that is squarely in this space and focused on leveraging new discoveries to target the activity of mTOR (mechanistic target of rapamycin). In many ways, the progress in the field has reached a tipping point and has prompted me to reflect on the advancements.

Chronic conditions of aging are the major cost drivers for healthcare. There are some shocking statistics to be found regarding the cost of chronic conditions affecting our healthcare system. The multiple chronic conditions chartbook published in 2010 by the Agency for Healthcare Research and Quality is a short and fascinating read. Almost half of all people aged 45-64, and 80% of those 65 and over, have multiple chronic conditions. 71 percent of US healthcare expenses go to treating people with multiple chronic conditions. Just take a moment to think about that. First off, this is a huge portion of our healthcare budget. It's not cancer. It's not rare diseases. It's not cosmetic or elective procedures. It's chronic illnesses, primarily associated with aging.

Id you have one disorder that is commonly associated with aging, chances are you have another or will develop another one. Basically, it's tough to get old. We all know that. But, now science is leading us to harness some fundamental mechanisms of aging. Two core aging mechanisms appear to have emerged as being accessible to new pharmacological intervention - the mechanistic target of rapamycin, or mTOR, and cellular senescence (which is wrapped up in mTOR as well). Drug development approaches using cellular senescence are emerging, and they are fascinating and worthy of attention. It's an exciting time in the aging space, and hopefully one that yields important new medications capable of reducing the personal, societal, and financial burdens of chronic diseases.

Cellular senescence is induced as a consequence of cellular damage accumulation, with the extent of activation directly depending on a fine-tuned balance between cellular conditions generating damage and those involved in counteracting them. The autophagic pathway plays a key role in preventing cell damage accumulation, however, the aging process leads to a decrease in autophagy capacity, and therefore also its effectiveness. In this context, senescence activation shows a more preponderant protective role.

The immune system does not escape from aging effects and displays senescence characteristics in aged individuals. Immunosenescence refers to the state of dysregulated immune function that contributes to the increased susceptibility to infections, autoimmune diseases, or cancer. Aged individuals are predisposed to more severe symptoms from certain infections and they do not mount an effective immune response upon vaccination. In general, aged populations fail to generate an appropriate innate and adaptive immune response against microorganisms, thus it becomes clear that senescence is involved in this failure.

Besides the normal occurrence of immunosenescence, several pathogen microorganisms accelerate the activation of senescence and predisposal to premature immunosenescence. For instance, hosts infected with bacteria such as P. aeuruginosa, M. tuberculosis, or H. pylori, some viruses, including HCMV, or the parasite T. cruzi, show characteristics of immunosenescence. A common issue of all of these pathogens is that they are able to generate chronic infections. In each of these, regardless of the fact that the host is faced with the same antigen several times during its lifetime, the immune response is inefficient. Furthermore, data shows that this condition generates an immune exhaustion and immunosenescence seems to be the major causative factor offering the pathogens an extra advantage since their elimination by the host tends to be even less effective.

Interestingly, a common characteristic of chronic infections is the autophagy blockage that usually occurs during autophagosome maturation, representing a factor that could contribute to or accelerate immunosenescence activation since it predisposes cells to damage accumulation. Deeper exploration to elucidate whether the activation of senescence in chronic infection is a consequence of autophagy impairment produced by pathogens to avoid degradation or, alternatively, whether it is a mechanism employed by the host to diminish infection spreading when the degradation of the pathogens has been halted. This exploration is needed to further understand the infection-autophagy-senescence relationship. With the available data, we hypothesize that chronic infections induce senescence with similar characteristics of aging, i.e., increase of inflammatory state and autophagy inhibition.

Mark Pepys, who has been working on amyloidosis for 43 years, discovered way back in the 1980s that SAP, a normal, nonfibrous circulating plasma glycoprotein, is involved in the formation of amyloid deposits. He went on to show it is always present as a minor component of human amyloid deposits of all types, and that it prevents amyloid fibrils from being cleared via opsonization and phagocytosis. Despite attracting the interest of big pharma, attempts to translate those insights to the clinic have been slow to bear fruit.

A collaboration with Roche Holding AG that started in 1993 led to the discovery of miridesap (then known as CPHPC). When tested in the rare disease systemic amyloidosis, miridesap removed SAP from the blood, but could not shift large deposits of amyloid from organs. Amyloidosis patients treated with miridesap remained stable, but the deposits did not disappear. After Roche handed back rights in 2008, Pepys formed a collaboration with Glaxosmithkline to develop miridesap in combination with an anti-SAP antibody for treating amyloidosis. The rationale was to remove SAP from the blood and then use the antibody to target SAP in amyloid, activating the complement system to clear the deposits. That played out in a phase I study published in 2015, but a phase II, 30-patient study of the combination therapy recently was suspended by GSK.

Meanwhile, Pepys has been pursuing development of miridesap as a monotherapy in Alzheimer's disease. His basis for thinking miridesap can remove amyloid from the brain when it was not effective in removing it from other organs, is related to the much lower level of SAP that needs to be sponged up. SAP is generated and catabolized only in the liver and is not expressed in the brain. In a mouse model of Alzheimer's that is genetically engineered to generate human SAP, depleting SAP in the bloodstream removed all detectable SAP from amyloid in the brain.

The study is funded with 6.2 million in grants from NIHR. GSK has no commercial interest, but has assisted with the logistics of setting up the Despiad (Depletion of serum amyloid P component in Alzheimer's disease) trial. Patients in the trial will be required to inject miridesap three times a day over 12 months and to undergo a wide range of tests, including PET scans, lumbar punctures, and cognitive assessments. Pepys hopes the 100-patient, double-blind, placebo-controlled Despiad trial, will show the reduction in SAP levels translates into clinical benefit.

Ectopic expression of hTERT, the catalytic sub-unit of telomerase, which can preserve telomere length and avert senescence of some cells. It was initially thought that the functional and physical deterioration that characterise organismal ageing are a result of insufficient replenishment of cells due to telomere-mediated restriction of cellular proliferation. Senescent cells, which accumulate increasingly in tissues in function of age, were assumed to be passive and merely a consequence of the above-described processes. This notion was short-lived when senescent cells were found to secrete molecules that are detrimental to cells and tissues.

As such, it would follow that if cells were prevented from becoming senescent in the first place, ageing could be avoided. Although there are external instigators such as stress and DNA damage that can also cause cells to become senescent, replicative senescence is particular in that it is an intrinsic feature that is part of cellular proliferation and occurs even in an ideal environment. As expression of hTERT has been repeatedly demonstrated to prevent replicative senescence of many different cell types, it is reasonable to consider ectopic expression or re-activation of endogenous hTERT expression as potential means to prevent replicative senescence, delay ageing, and improve health.

The above proposition would be valid if senescent cells were indeed the only cause of ageing. Relatively recently, an apparently distinct form of ageing, called epigenetic ageing was described. This discovery stems from observations that the methylation states of some specific cytosines that precede guanines (CpGs) in the human genome changed rather reliably and strictly with age. This allowed supervised machine learning methods to be applied to DNA methylation data to generate an DNA methylation-based age estimator, which in the majority of the human population is similar with chronological age. Epigenetic age is not merely an alternative means of determining chronological age but is to some degree a measure of biological age or health; a proposition that is further supported by the impressive demonstration that acceleration of epigenetic ageing is associated with increased risk of all-cause mortality.

We recently developed a new epigenetic age estimator, referred to as skin and blood clock that is more accurate in estimating age of different cell types including fibroblasts, keratinocytes, buccal cells, blood cells, saliva and endothelial cells. Studies employing skin and blood clock and the pan-tissue epigenetic age clock revealed a startling consistency of epigenetic age across diverse tissues from the same individual, even though cellular proliferation rates and frequencies of these tissues are not the same. This suggests that the ticking of the epigenetic clock is not a reflection of proliferation frequency, which is in stark contrast to telomere length, which enumerates cellular division. It would therefore appear that the process of epigenetic ageing is distinct from that which is driven by telomere-mediated senescence.

To understand their relationship or interaction, if one indeed exists, we set out to test the impact of hTERT on epigenetic ageing. To this end we employed wild type hTERT that can prevent telomere attrition and its mutants that cannot, with some still able to nevertheless prolong cellular lifespan. Expressing these hTERT constructs in primary cells from numerous donors, ages and cell types, we observe that while hTERT expression can indeed prevent cellular senescence, it does not prevent cells from undergoing epigenetic ageing and that extension of cellular lifespan is sufficient to support continued epigenetic ageing of the cell. These simple observations provide a very important piece to the puzzle of the ageing process because it reveals the distinctiveness of epigenetic ageing from replicative senescence-mediated ageing. They provide further empirical support to the epidemiological observation that hTERT variant that is associated with longer telomeres are also associated with greater epigenetic ageing.

The 3-D-printing method, which took two years to research, involves taking stem cells from the patient's own body fat and printing them on a layer of hydrogel to form a tendon or ligament which would later grow in vitro in a culture before being implanted. But it's an extremely complicated process because that kind of connective tissue is made up of different cells in complex patterns. For example, cells that make up the tendon or ligament must then gradually shift to bone cells so the tissue can attach to the bone. "This technique is used in a very controlled manner to create a pattern and organizations of cells that you couldn't create with previous technologies. It allows us to very specifically put cells where we want them."

To do that, the team used a 3-D printer typically used to print antibodies for cancer screening applications. The researchers developed a special printhead for the printer that can lay down human cells in the controlled manner they require. To prove the concept, the team printed out genetically-modified cells that glow a fluorescent color so they can visualize the final product. The technology is initially designed for creating ligaments, tendons and spinal discs, but in the future it could be adapted to any type of tissue engineering application, such as the 3-D printing of whole organs, an idea researchers have been studying for years.

As we get older, more and more of our the cells in our bodies become dysfunctional and enter into a state known as senescence. These senescent cells no longer divide or support the tissues and organs of which they are part; instead, they secrete a range of harmful inflammatory chemical signals, which are known as the senescence-associated secretory phenotype (SASP). Dr. Judith Campisi from the Buck Institute for Research on Aging, along with her research team, identified that senescent cells secreted the various harmful chemicals that characterize the SASP in 2008, which was when interest in senescent cells really began.

The SASP is a real problem: it increases inflammation, harms tissue repair and function, causes the immune system to malfunction, and raises the risk of developing age-related diseases such as cancer. Even worse, the SASP also encourages nearby healthy cells to become senescent, so even a very small number of senescent cells can cause big problems. Normally, senescent cells destroy themselves by a self-destruct process known as apoptosis or are cleared away by the immune system. Unfortunately, as we age, the immune system becomes weaker, and the senescent cells start to build up in the body. The accumulation of senescent cells is considered to be one of the reasons why we age and develop age-related diseases.

With these experiments, the biotechnology industry had initial proof that targeting one of the aging processes directly could improve health by delaying aging in mice; this began the search to develop therapies that target and destroy these harmful cells. This was the birth of a new class of drugs and therapies that would become known as senolytics. So far, there have been a number of drugs and naturally occurring compounds with senolytic potential and multiple mouse experiments demonstrating that the clearance of these cells can delay the onset of diseases such as cancer, heart disease, osteoporosis, arthritis, and Alzheimer's.

Interest in senolytics has seen a meteoric rise in the last couple of years, with investment money pouring in as confidence in the approach has reached new heights. There are also a number of companies developing therapies to destroy senescent cells, and it is likely that more will join them in the coming years. Leading the charge is Unity Biotechnology, which was founded in 2011 and has raised over 385 million in funding since then. Other companies are hot on its heels developing ways to seek and destroy these harmful cells. Oisin Biotechnologies, based in Seattle, is one such company. Founded in 2016, it has raised around 4 million to date and is developing a unique lipid nanoparticle-based system to deliver senolytic and cancer therapies. Cleara Biotech, based in the Netherlands, and Spain-based Senolytic Therapeutics are also busy developing senolytic therapies.

In 1989, the anti-aging and prolongevity actions of calorie restriction (CR) were explained from the evolutionary viewpoint of organisms having evolved adaptive response systems to maximize survival during periods of food shortage. On the basis of this evolutionary viewpoint, we divided the beneficial actions of CR into two systems; "systems activated under sufficient energy resource conditions" and "systems activated under insufficient energy resource conditions". The former is activated under natural environmental conditions that grant animals free use of energy by providing a plentiful food supply. In other words, when there is grace for free use of energy, animals grow well, reproduce more, and store excess energy as triglyceride in white adipose tissue for later use, but not to such an extent that they become obese. The latter is activated under natural environmental conditions that do not permit free use of energy because of food shortages.

In other words, when there is no grace for free use of energy, animals suppress growth and reproduction and shift energy use from growth and reproduction to maintenance of biological function, but not to such an extent that they become severely starved. Adaptation to natural environmental changes is a top priority for survival in animals. On the basis of the adaptive response hypothesis, we propose a suite of mechanisms for the beneficial actions of CR. Since experimental CR conditions can mimic insufficient energy conditions, we hypothesized that CR suppresses "systems activated under sufficient energy conditions" and activates "systems activated under insufficient energy conditions", and additively induces anti-aging and prolongevity actions. The first set of systems involves GH/IGF1, FOXO, mTOR, adiponectin and BMAL1 signaling, and CR appears to suppress these anabolic reactions. The second set of systems involves SREBP-1c/mitochondria redox, SIRT and NPY signaling, and it is likely that CR activates these reactions to make optimal use of insufficient energy resources.

Studies using monkeys suggest that the beneficial actions of CR may occur in humans as well as other mammals. Ongoing CR research focuses on two themes, i.e. elucidation of the molecular mechanisms of CR, and development of CR mimetic medicines. We consider development of novel CR mimetic medicines to be difficult without an understanding of the molecular mechanisms of CR. To develop CR mimetic medicines that are applicable to humans, further studies are therefore required on the molecular mechanisms of CR, particularly in non-human primates. In this report, we propose that the molecular mechanisms of beneficial actions of CR should be classified and discussed according to whether they operate under rich or insufficient energy resource conditions. Future studies of the molecular mechanisms of the beneficial actions of CR should also consider the extent to which the signals/factors involved contribute to the anti-oxidative, anti-inflammatory, anti-tumor and other CR actions in each tissue or organ, and thereby lead to anti-aging and prolongevity.

Mitochondria play an essential role in many important physiological processes, including aging. Mitochondrial function has been thought to gradually decline with age, while oxidative damage and mitochondrial DNA mutations accumulate. Although complete disruption of mitochondrial function is detrimental or even lethal for many eukaryotes, including humans, accumulating evidence has revealed that partial inhibition of mitochondrial function tends to increase lifespan. In C. elegans, mutations in various mitochondrial electron transport chain (ETC) genes can greatly extend lifespan; these include mutations in isp-1 and clk-1. In addition, RNAi knockdown of various mitochondrial ETC genes prolongs lifespan in yeast, worms, and fruit flies.

The effects of mitochondrial ETC genes on modulating lifespan appear to be complex. Inhibition of some ETC genes increases lifespan, whereas inhibition of others decreases or does not alter lifespan in C. elegans and Drosophila. For example, mutations in mev-1, which encodes a subunit of complex II, causes a short lifespan in worms. In addition, the underlying causes for lifespan regulation by ETC genes remain incompletely understood. For example, the roles of reactive oxygen species (ROS) production and mitochondrial function in aging and lifespan of ETC mutants can be opposite ways. One model interpreting these opposite effects is that moderate mitochondrial impairments increase lifespan until a threshold is reached, beyond which animals display wide-spread damage, shortened lifespan, or even death. Nevertheless, how mitochondrial genes modulate lifespan and whether they function in modulating lifespan in other species remain incompletely elucidated.

ATP synthase, also known as complex V of the mitochondrial respiratory chain, is the primary cellular energy-generating machinery. In mammals, ATP synthase deficiency is one of the rarer mitochondrial oxidative phosphorylation deficiencies. ATP synthase is also intimately linked to aging. In worms, genetic inhibition of the atp-2 gene, which encodes a subunit in complex V, leads to developmental delay and increased lifespan. Additionally, a genome-wide RNAi screen revealed that RNAi knockdown of subunits atp-3, atp-5, or asb-2 prolongs worm lifespan. However, the underlying mechanism for lifespan extension due to inhibition of these subunits in the ATP synthase remains unclear. As ATP synthase is highly conserved throughout evolution, understanding the role of the ATP synthase in lifespan regulation can lead to untangling of the complexity of mitochondrial ETC genes in modulating lifespan.

The gut microbiota (GM) largely derives nutrients from dietary intake. In this respect, a large number of studies have been reported on the variations of the GM composition occurring according to different diets. The majority of these studies have focused on the comparison of low vs. high energy density (i.e., high fat or high sugar) diets in animals fed ad libitum (AL), showing an increase in the Firmicutes/Bacteroidetes ratio and the proliferation of pro-inflammatory Proteobacteria in the latter condition.These changes occur rapidly and can be partially restored by reverting to the control diet. Animal experimental data also agree with observational studies in humans, where similar taxonomic features were found to be changed between obese and lean individuals.

In addition, the GM composition varies rapidly and significantly in response to macronutrient changes, even when equal numbers of calories are provided. This clearly suggests that the relative abundance of the specific GM members strongly depends on the quality of nutrients they have access to. Hence, given the strong relationship among diet, GM and health, there is a growing interest in developing novel dietary strategies to modulate the composition and, possibly, the metabolic functions of the GM.

Among dietary interventions, caloric restriction (CR) is well known for the health-promoting impact on lipid metabolism and longevity. CR is generally applied without changing the macronutrient composition and solely reducing the caloric intake compared to the AL condition. As a consequence, in experimental models, caged individuals fed a CR diet consume completely their food and then fast for several hours before the next feed administration. We have recently reported that CR induces a rapid change (as early as after 3 weeks of CR) of the GM composition in young rats, that parallels a reduction of triglycerides and cholesterol levels in the blood, and that these changes are maintained up to mid age. In particular, a CR diet enabled the expansion of Lactobacillus rapidly and persistently up to adulthood. CR-induced variation of the GM composition might then play a role in helping extend lifespan and delay the onset of age-related disorders by preserving gut homeostasis. However, the precise biochemical changes the GM undergoes during CR are still undetermined, in the short and in the long term.

Here, we investigated the short- and long-term effects of CR on the rat GM using a metaproteogenomic approach. We show that a switch from ad libitum (AL) low fat diet to CR in young rats is able to induce rapid and deep changes in their GM metaproteomic profile, related to a reduction of the Firmicutes/Bacteroidetes ratio and an expansion of lactobacilli. Specifically, we observed a significant change in the expression of the microbial enzymes responsible for short-chain fatty acid biosynthesis, with CR boosting propionogenesis and limiting butyrogenesis and acetogenesis.

The integrity of the musculature and the muscle strength is of great importance throughout the entire life span. Age-related decreases in muscle mass and strength are also associated with morphological losses in the brain and decreased cognitive functions. There is growing evidence with respect to positive effects of physical activity preventing and treating morphological and functional losses in muscles and the brain. In recent years, evidence has emerged emphasizing the existence of a bidirectional relationship between physical performance and brain health. The bidirectional relationship suggests that physical training may be a valuable intervention strategy to decelerate not only physical but also cognitive decline in old age. However, the exercise type (e.g., resistance training, endurance training) and exercise variables (e.g., load, duration, frequency), which would be optimal to efficiently enhance cognitive performance are largely unknown.

A promising and cost-effective physical intervention strategy which preserves and enhances both, physical performance (especially with regard to the musculature) and cognitive functions, is resistance training (also known as strength training). A relative new method in the field of resistance training is blood flow restriction training (BFR). While resistance training with BFR is widely studied in the context of muscular performance, this training strategy also induces an activation of signaling pathways associated with neuroplasticity and cognitive functions. Based on this, it seems reasonable to hypothesize that resistance training with BFR is a promising new strategy to boost the effectiveness of resistance training interventions regarding cognitive performance.

This was the first study to forecast a comprehensive set of cause-specific and all-cause mortality and associated indicators using a framework that allows for exploring different scenarios for many risk factors and other independent drivers. In our reference scenario, life expectancy was forecasted to continue increasing globally, and 116 of 195 countries and territories were projected to have significant advances in life expectancy by 2040. Gains were projected to be faster among many low-to-middle SDI countries, indicating that inequalities in life expectancy could narrow by 2040.

As shown by the better health scenarios, greater progress might be possible, yet for some drivers such as high body-mass index (BMI), their toll will rise in the absence of intervention. We forecasted global life expectancy to increase by 4.4 years for men and 4.4 years for women by 2040, but based on better and worse health scenarios, trajectories could range from a gain of 7.8 years to a non-significant loss of 0.4 years for men, and an increase of 7.2 years to essentially no change (0.1 years) for women.

In 2040, Japan, Singapore, Spain, and Switzerland had a forecasted life expectancy exceeding 85 years for both sexes, and 59 countries including China were projected to surpass a life expectancy of 80 years by 2040. At the same time, Central African Republic, Lesotho, Somalia, and Zimbabwe had projected life expectancies below 65 years in 2040, indicating global disparities in survival are likely to persist if current trends hold.

Taken together, our forecasts point to a world where most populations are living longer and many health improvements are likely to occur if current trajectories hold; at the same time, such gains are not without potential important social consequences, particularly if long-term planning and policy design are not fully considered today.

An important finding is that in the reference scenario, we forecasted slower progress in 2040 than that achieved in the past; however, in the better health scenario, global life expectancy improvements exceeded gains that occurred from 1990-2016. This forecasted slowdown in the reference scenario is rooted in a combination of several factors. First, some risks were projected to worsen in the future, most notably high BMI. Second, past progress on other leading risk factors for premature mortality, namely tobacco and ambient particulate matter air pollution, was highly variable and thus such heterogeneity was projected through 2040. Third, several countries that have already achieved higher levels of life expectancy have also had stagnated gains.

Hypertension is a modifiable risk factor for cardiovascular disease and exercise is widely recommended for hypertensive patients as a lifestyle modification because of the well-documented beneficial effect of exercise on lowering blood pressure (BP). Similarly, calorie restriction, although not widely recommended for patients, is also documented to lower hypertension. Interestingly, both exercise and calorie-restriction are associated with increased circulating levels of ketone bodies such as β-hydroxybutyrate (βOHB). βOHB is produced predominantly in the liver, transported to other tissues, and traditionally recognized as a vital alternative metabolic fuel during times of starvation. However, contemporary evidence indicates that apart from serving as energy fuels, ketone bodies such as βOHB block inflammasome-mediated inflammatory diseases and thereby play a prominent role in maintaining physiological homeostasis.

In contrast to exercise and calorie-restriction, consumption of high salt promotes hypertension. Studies on the effects of dietary salt have focused mainly on organs and tissues relevant to BP regulation such as kidney, vasculature, heart, and brain. A recent report suggests that a reduction in salt intake serves as an additional interventional approach for reducing the risk for developing metabolic syndrome, of which, hypertension is one of the hallmark features. Taken together, these studies point to an intriguing possibility that a high salt diet induced a deleterious effect on hypertension and could mechanistically represent the opposite scenario to that of the protective effects of exercise and calorie-restriction on hypertension by altering the levels of metabolites such as ketone bodies.

Here, we examined this possibility, first by an untargeted mass spectrometry-based plasma metabolomics study and discovered altered ketogenesis and over-activation of renal Nlrp3 as a key mechanistic link between high salt and hypertension. These results indicated that a high salt diet has mechanistically opposite effects of exercise and calorie-restriction on BP. Next, we demonstrated that nutritional intervention with 1,3-butanediol, a precursor of the endogenous ketone body, βOHB, reversed the adverse effects of high salt induced renal Nlrp3-mediated inflammation, fibrosis, and hypertension. Based on these observations in the Dahl S rat, which is a salt-sensitive pre-clinical model of hypertension, we propose dietary intervention with 1,3-butanediol as an intriguing strategy for the clinical management of salt-sensitive hypertension.

Somatic stem cells are microscopic workhorses, constantly regenerating cells throughout the body: skin and the lining of the intestine, for example. Researchers have demonstrated for the first time that stem cell proliferation is directly controlled by the autonomic nervous system (ANS). The ANS controls all of our unconscious functions: breathing, blood flow, digestion, and so forth. Its two major networks of nerve fibers run from the brain through the entire body, with neurons reaching into nearly every organ. These neurons release chemicals called neurotransmitters, which can affect target cells directly or indirectly.

When neurotransmitters bind to receptors in the membranes of certain cells, they elicit a direct response within the cell. But changes in cells can also occur when neurotransmitters induce a general state of inflammation or alter blood flow, an indirect route of action for the ANS. Scientists had suspected the ANS was involved in stem cell proliferation, but they didn't know if the relationship was direct or indirect. A direct relationship could have greater implications for drug interventions to treat medical conditions. "If you wanted to change the regeneration potential of an organ, for example, you wouldn't have to stimulate or suppress the activity of those neurons. Instead, you could just figure out what neurotransmitters are controlling proliferation and then get that chemical to those stem cells with targeted drug delivery."

To demonstrate that stem cell behavior was changing as a result of ANS stimulation, the researchers grew intestinal epithelial cells in the lab and exposed them to high levels of two neurotransmitters, norepinephrine and acetylcholine. Norepinephrine is a major neurotransmitter of the sympathetic nervous system, or "fight or flight" branch of the ANS, while acetylcholine is produced by the parasympathetic nervous system, or "rest and digest" branch. When the researchers simulated activation of either of those systems, they saw a decrease in stem cell proliferation. This suggests the body may avoid putting energy into making new cells when the fight or flight system is active.

Hearing impairment has long been accepted as a fact of life for the aging population - an estimated 30 million Americans suffer from some degree of hearing loss. However, scientists have long observed that other animals - namely birds, frogs, and fish - have been shown to have the ability to regenerate lost sensory hair cells. "It's funny, but mammals are the oddballs in the animal kingdom when it comes to cochlear regeneration. We're the only vertebrates that can't do it."

In 2012 researchers identified a family of receptors - called epidermal growth factor (EGF) - responsible for activating support cells in the auditory organs of birds. When triggered, these cells proliferate and foster the generation of new sensory hair cells. The researchers speculated that this signaling pathway could potentially be manipulated to produce a similar result in mammals. "In mice, the cochlea expresses EGF receptors throughout the animal's life, but they apparently never drive regeneration of hair cells. Perhaps during mammalian evolution, there have been changes in the expression of intracellular regulators of EGF receptor family signaling. Those regulators could have altered the outcome of signaling, blocking regeneration. Our research is focused on finding a way switch the pathway temporarily, in order to promote both regeneration of hair cells and their integration with nerve cells, both of which are critical for hearing."

In a new study, researchers tested the theory that signaling from the EGF family of receptors could play a role in cochlear regeneration in mammals. The researchers focused on a specific receptor called ERBB2 which is found in cochlear support cells. One set of experiments involved using a virus to target ERBB2 receptors. Another involved mice genetically modified to overexpress an activated ERBB2. A third experiment involved testing two drugs, originally developed to stimulate stem cell activity in the eyes and pancreas, that are known activate ERBB2 signaling. The researchers found that activating the ERBB2 pathway triggered a cascading series of cellular events by which cochlear support cells began to proliferate and start the process of activating other neighboring stem cells to become new sensory hair cells. Furthermore, it appears that this process not only could impact the regeneration of sensory hair cells, but also support their integration with nerve cells.