Longevity scientists who favor the idea of living for centuries or longer tend to speak effusively of prosperity and possibility. As they see it, sustaining life and promoting health are intrinsically good and, therefore, so are any medical interventions that accomplish this. Biomedically extended longevity would not only revolutionize general well-being by minimizing or preventing diseases of aging, they say, it would also vastly enrich human experience. It would mean the chance for several fulfilling and diverse careers; the freedom to explore much more of the world; the joy of playing with your great-great-great-grandchildren; the satisfaction of actually sitting in the shade of the tree you planted so long ago. Imagine, some say, how wise our future elders could be. Imagine what the world's most brilliant minds could accomplish with all that time.

In sharp contrast, other experts argue that extending life span, even in the name of health, is a doomed pursuit. Perhaps the most common concern is the potential for overpopulation, especially considering humanity's long history of hoarding and squandering resources and the tremendous socioeconomic inequalities that already divide a world of nearly eight billion. There are still dozens of countries where life expectancy is below 65, primarily because of problems like poverty, famine, limited education, disempowerment of women, poor public health and diseases like malaria and H.I.V./AIDS, which novel and expensive life-extending treatments will do nothing to solve. Lingering multitudes of superseniors, some experts add, would stifle new generations and impede social progress.

Although the pace of senescence varies considerably, the physiological systems that contribute to different patterns of senescence are not well understood, especially in long-lived vertebrates. Long-lived bony fish (i.e., Class Osteichthyes) are a particularly useful model for studies of senescence because they can readily be aged and exhibit some of the longest lifespans among vertebrates. In this study we examined the potential relationship between age and multiple physiological systems including: stress levels, immune function, and telomere length in individuals ranging in age from 2 to 99 years old in bigmouth buffalo (Ictiobus cyprinellus), the oldest known freshwater teleost fish.

Contrary to expectation, we did not find any evidence for age-related declines in these physiological systems. Instead, older fish appeared to be less stressed and had greater immunity than younger fish, suggesting age-related improvements rather than declines in these systems. There was no significant effect of age on telomeres, but individuals that may be more stressed had shorter telomeres. Taken together, these findings suggest that bigmouth buffalo exhibit negligible senescence in multiple physiological systems despite living for nearly a century.

The study of human extreme longevity constitutes a model useful to assess the impact of genetic variability on this trait according to the following considerations. First, researchers showed that, considering individuals surviving to age 105 years, the relative risk of sibling surviving to 105 years is 35 times the chance of living to age 105 of the control population. These data suggest a more potent genetic contributions if samples are recruited in the last percentile of survival - the power to detect association with longevity is greater for centenarians versus nonagenarians samples of the same birth cohort. Second, despite different definitions and opinion regarding the concept of healthy aging, the clinical and biochemical data on centenarians showed that they can be considered as a paradigm of healthy aging as they avoid or largely postpone all major age-related diseases. Thus, healthy aging and exceptional longevity (people who live more than 100 years) are deeply related.

Cardiovascular diseases (CVDs) constitute the first cause of death globally and many studies highlighted the intersection between CVDs and aging as cardiac and vascular aging are considered the major risk factor for CVDs. Many molecular mechanisms have been described as hallmarks of this process such as cellular senescence, genomic instability, chromatin remodeling macromolecular damage, and mitochondrial oxidative stress, perturbed proteostasis, vascular and systemic chronic inflammation, among others. An emerging common mechanism between aging and CVD is the accumulation with age of somatic mutations. An age-related expansion of hematopoietic clones characterized by disruptive somatic mutations in few recurrent genes (such as DNMT3A, TET2, ASXL1, PPM1D, TP53), conferring to the mutated cells a selective proliferative advantage. The expansion of such mutated clones ('clonal hematopoiesis of indeterminate potential', CHIP), has been associated to an acceleration of the atherosclerotic process, an increased risk of haematological malignancies, ischemic stroke, coronary heart disease, and all-cause mortality.

In this study, we generated and analyzed the first whole genome sequencing data with high coverage (90X) in a cohort of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) recruited across the entire Italian peninsula together with a control cohort of 36 healthy geographically matched individuals (Northern, Central, and Southern Italy) (mean age 68.0 ± 5.9). Data recently published with a second independent cohort of 333 centenarians (100+ years) and 358 geographically matched controls (Northern, Central, and Southern Italy) were used to replicate our results.

We identified five common variants (rs7456688, rs10257700, rs10279856, rs69685881, and rs7805969), all in the same region located between COA1 gene and STK17A gene. The gene-based analysis of sequencing data identified STK17A gene as the most significant gene that is validated in the second cohort.

STK17A is involved in DNA damage response and positive regulation of apoptotic process and regulation of reactive oxygen species (ROS) metabolic process. Moreover, it has been suggested that STK17A can be activated in response to external stimuli such as UV radiation and drugs. Data suggests a possible role of this gene in DNA damage response as the variants associated to an increase of SKT17A expression (in-silico prediction) were found more frequent in 105+/110+ than controls. Researchers have proposed the following sequence of events that occurs during aging: (i) mutation impairs function of genes involved in stress response and DNA repair; (2) DNA repair became more error-prone leading to accumulation of DNA damage; (3) this process accelerates age-related decline. In this model, genetic variants in STK17A may maintain DNA damage responses in 105+/110+, favoring healthy aging.

Our field is divided into two groups of people. The first group consists of the snake oil salesmen peddling unproven supplements and therapies to whoever is foolish enough to buy and take things on faith without using the scientific method. The hucksters have long been a plague on our field, preying on the gullible and tainting legitimate science with their charlatanry and nonsense. One example is a "biotech company" evading the FDA by setting up shop in countries with few or no regulations. They make bold claims yet never deliver on those claims in practice, using poorly designed experiments and tiny cohorts that are statistically irrelevant.

Another example is the supplement peddler selling expensive supplement blends with flashy names, which, on inspection, turn out to be commonly available herbs and minerals that are mixed and sold at a high markup with questionable or no supporting data. These sorts of people have plagued our community and given the field a reputation of snake oil.

The second group are the credible scientists, researchers, and companies who have been working on therapies for years and sometimes more than a decade or two. Some of these therapies are following the damage repair approach advocated by Dr. Aubrey de Grey of the SENS Research Foundation over a decade ago. The basic idea is to take an engineering approach to the damage that aging does to the body and to periodically repair that damage in order to keep its level below that which causes pathology. Others including Dr. David Sinclair are focusing on partial cellular reprogramming and believe it may be possible to reset the cells in our bodies to a younger state using reprogramming factors.

While it will be some years yet before all therapies to end age-related diseases are here and available, and the hucksters are still peddling their wares, you can arm yourself with knowledge and protect yourself and our community from these people. Learn to evaluate science rather than taking things at face value, and avoid expensive scams and bad science. Here is a useful checklist to consider when reading an article, looking at claims made by supplement makers, or evaluating any science in general.

Abnormal buildup of amyloid-beta is one hallmark of Alzheimer's disease. The brain's lymphatic drainage system, which removes cellular debris and other waste, plays an important part in that accumulation. A 2018 study showed a link between impaired lymphatic vessels and increased amyloid-beta deposits in the brains of aging mice, suggesting these vessels could play a role in age-related cognitive decline and Alzheimer's. The lymphatic system is made up of vessels which run alongside blood vessels and which carry immune cells and waste to lymph nodes. Lymphatic vessels extend into the brain's meninges, which are membranes that surround the brain and spinal cord.

For this new study, the research team sought to determine whether changing how well the lymphatic drainage works in the brain could affect the levels of amyloid-beta and the success of antibody treatments that target amyloid-beta. Using a mouse model of early-onset Alzheimer's, researchers removed some of the lymphatic vessels in the brains of one group of mice. They treated these mice, as well as a control group, with injections of monoclonal antibody therapies, including a mouse version of aducanumab.

Mice with less functional lymphatic systems had greater buildup of amyloid-beta plaques and of other immune cells that cause inflammation, which is another factor in Alzheimer's pathology. Moreover, when the researchers compared immune cells in the brains of human Alzheimer's patients with those of the mice whose meningeal lymphatic system had been diminished, they found that the genetic fingerprints of certain immune cells in the brain, the microglia, were very similar between people with the disease and mice with defective lymphatic vessels. These mice also performed more poorly on a test of learning and memory performance, suggesting that dysfunctional lymphatic drainage in the brain contributes to cognitive impairment and increases difficulties for antibodies that target amyloid-beta.

Alzheimer's disease (AD) is the most prevalent cause of dementia. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD.

Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD.

Overall, our data demonstrate that impaired meningeal lymphatic drainage can exacerbate the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.

Experiments in experimental rodents and observations in human volunteers or patients suggest that the beneficial effects of intermittent fasting can only partly be explained by reduced calorie intake. A plethora of alternative mechanisms mediating the effects of intermittent fasting have been brought forward and can roughly be grouped in three categories that involve mechanisms involving circadian biology, altered lifestyle, and remodeling of the gut microbiome.

The notion that the latter is especially instrumental for mediating the beneficial effects of intermittent fasting is supported by many observations in experimental animals, including that white adipose tissue browning provoked by intermittent fasting requires an intestinal flora, or that restructuring of the gut microbiome by intermittent fasting counteracts retinopathy in diabetic mice. The effects of intermittent fasting on the human microbiome remain, however, largely uncharacterized, and in view of the problems associated with extrapolating data in experimental rodents to humans, it would be important to establish the effects of intermittent fasting in our species as well.

Prompted by the above mentioned considerations, we decided to characterize the effects of a monthly episode of intermittent fasting on the human gut microbiome and to contrast the results with nonfasting controls and with the effects of cessation of intermittent fasting following the intervention.

We observed in two independent cohorts, sampled in two different years, that Ramadan-associated intermittent fasting induces substantial remodeling of the gut microbiome. Importantly, we established that intermittent fasting in humans is especially associated with an upregulation of butyric acid-producing Lachnospiraceae in a manner that correlates to improvement in human physiologic surrogate markers such as blood glucose and BMI. Intermitting fasting-provoked upregulation of Lachnospiraceae thus may provide a rational explanation for at least some of the beneficial effects reported for intermittent fasting in humans.

A protein called IL-24 attacks a variety of cancers in several different ways. Researchers now deliver the gene coding for IL-24, which is called MDA-7, to solid tumors using T cells. This isn't the first time T cells have been engineered for cancer immunotherapy. Chimeric antigen receptor T (CAR-T) cell therapy - which is designed to destroy cancer cells expressing specific surface molecules - has shown tremendous success for treating advanced cancers of the blood and lymphatic systems. But CAR-T has made limited progress on solid tumors, such as prostate cancer or melanoma, because the cells that make up those tumors aren't all the same, which blocks the engineered T cells from recognizing and attacking. Researchers armed T cells with MDA-7/IL-24 to target cancer more broadly.

At the sub-cellular level, MDA-7/IL-24 binds to receptors on the surface of cells and instructs them to make and release more copies of the MDA-7/IL-24 protein. If the cell is normal, the protein is simply secreted and no damage occurs. But if the cell is cancerous, MDA-7/IL-24 causes oxidative stress damage and ultimately cell death, not only within the primary tumor but also among its distant metastases - the cause of death in 90% of patients. As a result of this process, the immune system generates memory T cells that can theoretically kill the tumor if it ever comes back. At the whole tumor level, IL-24 also blocks blood vessel formation, starving tumors of the nutrients so badly needed to sustain their unchecked growth.

In mice with prostate cancer, melanoma, or other cancer metastases, MDA-7/IL-24-expressing T cells slowed or stopped cancer progression better than unmodified T cells. The researchers also discovered that arming T cells with MDA-7/IL-24 allowed them to survive better and multiply in the tumor microenvironment - the space right around the cancerous mass. In the clinic, this approach would involve extracting the patient's own T cells from tumor samples, genetically engineering them to express MDA-7/IL-24, growing millions of copies of the cells in the lab and finally transplanting them back into the patient. CAR-T cells could also be engineered to express MDA-7/IL-24.

In this prospective cohort study, we linked data from Norwegian population-based health examination surveys, covering all parts of Norway with data from the National Population and Housing Censuses and the Norwegian Cause of Death Registry. 437,378 participants (aged 18-65 years; 48.7% men) self-reported occupational physical activity (mutually exclusive groups: sedentary, walking, walking and lifting, and heavy labour) and were followed up from study entry (between February, 1974, and November, 2002) to death or end of follow-up on Dec 31, 2018, whichever came first. We estimated differences in survival time (death from all causes, cardiovascular disease, and cancer) between occupational physical activity categories by using flexible parametric survival models that were adjusted for confounding factors.

During a median of 28 years from study entry to the end of follow-up, 74 ,203 (17.0%) of the participants died (all-cause mortality), of which 20,111 (27.1%) of the deaths were due to cardiovascular disease and 29,886 (40.3%) were due to cancer. Crude modelling indicated shorter mean survival times among men in physically active occupations than in those with sedentary occupations. However, this finding was reversed following adjustment for confounding factors (birth cohort, education, income, ethnicity, prevalent cardiovascular disease, smoking, leisure-time physical activity, body-mass index), with estimates suggesting that men in occupations characterised by walking, walking and lifting, and heavy labour had life expectancies equivalent to 0.4, 0.8, and 1.7 years longer, respectively, than men in the sedentary referent category. Results for mortality from cardiovascular disease and cancer showed a similar pattern. No clear differences in survival times were observed between occupational physical activity groups in women.

Our results suggest that moderate to high occupational physical activity contributes to longevity in men. However, occupational physical activity does not seem to affect longevity in women. These results might inform future physical activity guidelines for public health.

One of the key stumbling blocks in the field of senescence is the lack of a single, universal, robust, biomarker that allows identification of senescent cells with high sensitivity and specificity and is capable of differentiating them from terminally differentiated, quiescent, and other non-dividing cells. Growth arrest is a key feature which can be readily demonstrated in vitro using assays that measure DNA synthesis. However, DNA synthesis measurement is not totally specific since DNA repair may still be active. Measuring the expression levels of p16INK4A and p21WAF1/CIP1 are key to detecting cell cycle arrest but are not expressed persistently particularly p21WAF1/CIP1 by senescent cells. Accumulation of high levels of p16INK4A is required to maintain the senescent state enabling it to be extensively used as a marker for senescence in most normal untransformed cells and tissues. However, p16INK4A is also expressed in non-senescent cells and cells that are transiently arrested, and senescence can also occur independently of p16INK4A. Coupled with the lack of specific antibodies, this limits its use as a biomarker for senescence.

Accumulating evidence has demonstrated that both anti-senescence and pro-senescence therapies could be beneficial depending on the context. Pro-senescence therapies help limit damage by restraining proliferation and fibrosis during carcinogenesis and active tissue repair whereas anti-senescence agents enable elimination of accumulated senescent cells to restore tissue function, and potentially aid organ rejuvenation. It has been found that cells which escape from senescence post-chemotherapy re-enter the cell cycle, are highly aggressive, chemo-resistant, and exhibit stem cell characteristics and can contribute to cancer recurrence. Since several therapeutic modalities trigger senescence in tumors, it is important to decipher the mechanisms involved in the escape from senescence as a more detailed understanding may allow the development of better therapies and also help to reduce the off-target effects contributing to unwanted toxicity.

A thorough understanding of SASP regulation is required to exploit it for therapeutic purposes. There is a growing need for further research to investigate how the different signaling pathways regulating SASP such as p38MAPK, mTOR, GATA4, TAK1, cGAS/cGAMP/STING are interconnected and how SASP manifests the age-related pathologies. Inhibition of SASP without perturbing the stable growth arrest would allow reduction of the deleterious effects while maintaining tissue homeostasis and other physiological roles. However, targeting SASP for therapeutic purposes has to be undertaken with great care since it has both beneficial and deleterious roles due to the plethora of components.

Identification of key SASP factors secreted by senescent cells in aged tissues and residual tumors in the post-treatment period might have potential as biomarkers for real-time medical surveillance. The advent of powerful genetic and pharmacological tools to dissect the relationship between accumulated senescent cells and aging should improve our understanding of how accumulated senescent cells lead to age associated decline.

A new study has found that people with reduced kidney function may have an increased risk of developing dementia. Chronic kidney disease affects approximately 15% of adults in the United States and it is more common as people age. However, since many people don't experience symptoms until later stages, it is estimated that 90% of people with chronic kidney disease don't know they have it. "Even a mild reduction in kidney function has been linked to an increased risk of cardiovascular disease and infections, and there is growing evidence of a relationship between the kidneys and the brain."

Researchers used a database to identify nearly 330,000 people 65 years and older who received health care in the city of Stockholm and were followed for an average of five years. None of the participants had dementia or had undergone kidney transplants or dialysis at the start of the study. Over the course of the study 18,983 people, or 6% of participants, were diagnosed with dementia.

Researchers found as kidney function decreased, the rate of dementia increased. In people with a normal kidney filtration rate of 90 to 104 mL per minute, there were seven cases of dementia per 1,000 person-years. In people with severe kidney disease, or a filtration rate of less than 30 mL per minute, there were 30 cases of dementia per 1,000 person-years.

After adjusting for other factors that could affect dementia risk like smoking, alcohol use, hypertension and diabetes, researchers determined that people with filtration rates of 30 to 59 mL per minute, which indicates moderate chronic kidney disease, had a 71% higher risk of developing dementia compared to those with normal kidney function, and people with filtration rates of less than 30 mL per minute had a 162% higher risk.

The Long Life Family Study (LLFS) has enrolled over 5,000 participants from almost 600 families and has been following them for the past 15 years. The study is unique in that it enrolls individuals belonging to families with clusters of long-lived relatives. Since 2006, the LLFS has recruited participants belonging to two groups: the long-lived siblings (also called the proband generation) and their children. Since they share lifestyle and environmental factors, the spouses of these two groups have also been enrolled in the LLFS as a referent group.

To assess cognitive performance, the researchers administered a series of assessments to the study participants meant to test different domains of thinking, such as attention, executive function and memory, over two visits approximately eight years apart. This allowed researchers to ask whether individuals from families with longevity have better baseline cognitive performance than their spouses do and whether their cognition declines more slowly than does that of their spouses.

Individuals from long-lived families performed better than their spouses on two tests: a symbol coding test, which has participants match symbols to their corresponding numbers and provides insight into psychomotor processing speed, attention, and working memory, and a paragraph recall test, which asks participants to remember a short story and assesses episodic memory. Individuals in the younger generation (participants born after 1935) exhibited a slower rate of cognitive decline on the symbol coding test than did their spouses.

"This finding of a slower decline in processing speed is particularly remarkable because the younger generation is relatively young at an average age of 60 years and therefore these differences are unlikely to be due to neurodegenerative disease. Rather we are detecting differences in normal cognitive aging."

Microglia, far from being simply 'brain glue', play an important role as the brain's resident immune cells. There is some precedent for the toxicity of senescent cells, with several studies identifying that the elimination of senescent cells as potential mechanisms for countering their deleterious effects. In the case of microglia, senescence as a descriptor is sometimes used interchangeably with dystrophic. 'Dystrophy' now tends to refer more to morphological changes, whereas 'senescence' may be used to refer to specific secretory phenotypes, particularly associated with ageing. These features have been observed in healthy but aged brains, although it has also been suggested by a study using human brain tissue that senescent microglia are exclusively a disease-associated phenotype.

Specific depletion of microglia by targeting of Colony Stimulating Factor 1 Receptor (CSF1R) has been utilised in mouse models, for the purpose of impeding the propagation of phospho-tau, such as is observed in Alzheimer's disease. However, even as this demonstrates the principle of specifically targeting microglia, such a large scale depletion of the cell type is likely to be of limited practical benefit in a clinical setting. CSF1R inhibition in mouse models has been shown to eliminate 99% of CNS microglia. Inhibition of CSF1R, then removal of this inhibition for 1 week, was demonstrated to allow 'repopulation' of microglia, while triggering no cognitive, motor function, or behavioural deficits.

It remains to be seen if this approach would be so successful in the larger, more complex human brain, where cell volume is substantially greater than in the mouse. Microglial elimination and repopulation in an aged mouse model was shown to improve cognition, particularly spatial memory, concurrently increasing density of synaptic spines and neurogenesis. These processes are diminished in the aged brain, demonstrating benefit not only to the microglia but also to the surrounding neurons.

Targeting and eliminating or reprogramming aged or senescent microglia clearly holds potential for reversing the impact of ageing on the brain, and much has already been learned from such techniques. However, at the present time, it remains unclear how these techniques might be translated into benefit in human patients. An ideal outcome would be the ability to target specifically aged, senescent, and neurotoxic microglia and eliminate them from the brain without the requirement for genetic manipulation and transgene expression. Efficacy of such a technique may well be improved by more specific identification and targeting of senescent microglia, which would require the identification of a unique, specific marker.

As we age, we become increasingly vulnerable to age-related diseases. The progressive aging of the population makes this issue one of, if not the, major current scientific concern in the field of medicine. Aging is an intricate process that increases the likelihood of cancer, cardiovascular disorders, diabetes, atherosclerosis, neurodegeneration, and age-related macular degeneration. The regenerative capacity of cells and tissues diminishes over time and they thus become vulnerable to age-related malfunctions that can precipitate death.

Developing prophylactic strategies to increase the duration of healthy life and promote healthy aging is challenging, as the mechanisms causing aging are poorly understood, even if great progress has been made from studying naturally occurring or accelerated-aging phenomena. We now know that aging inculcates many changes, or 'hallmarks': genomic instability, telomere shortening, epigenetic alterations, loss of proteostasis, cellular senescence, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular communication, and stem cell compromise and exhaustion. These various hallmarks of aging are all active fields of molecular mechanistic study with much promise but relatively few tangible results have been translated into therapy.

Perhaps the most effective strategies so far have been those that focus on the removal of senescent cells with 'senolytic' drugs. In some ways, however, we feel this is too focused on the symptoms of aging whereas perhaps the most promising strategy for the future would be to focus on the causes of aging and its corollary, the rejuvenative capacity of stem cells.

Simply expressing four transcription factors, OCT4, SOX2, KLF4 and c-MYC (OSKM), converts somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming occurs through a global remodeling of the epigenetic landscape that ultimately reverts the cell to a pluripotent embryonic-like state, with properties similar to embryonic stem cells (ESCs). This cellular reprogramming allows us to imagine cell therapies that restore organ and tissue function. Indeed, by reprogramming a somatic cell, from a donor into iPSCs, these cells can then be modified or corrected before redifferentiation, to produce 'rejuvenated' cells, tissues or organs, for replacement in the same donor or an immune-compatible person.

In recent years, emerging results have led to new ideas demonstrating that the mechanics of cellular reprogramming can be used to reduce the deleterious effects of aging and to delay these effects by increasing regenerative capacity, either at the cellular or the whole-organism level.

The inflammatory response that occurs systemically and in the brain is exacerbated as a result of aging. The underlying inflammation, which is actually heightened with age, is believed to be a precursor to neurodegenerative diseases like Alzheimer's disease. Moreover, in diseases in which inflammation plays a critical role, the aging population seems to be more vulnerable.

Previous research has shown that systemic infection can affect the central nervous system (CNS); studies have shown evidence of cognitive decline following systemic inflammation. Cognitive decline seems to occur more frequently in the aged population after infection, likely due to the microglial priming that occurs with age. Primed microglia have a heightened pro-inflammatory gene profile and a decrease in neuroprotective factors, which causes an exaggerated response to stimuli. Based on this evidence, it was hypothesized that systemic infection would produce a greater pro-inflammatory response in the brain of aged mice, and that this heightened response occurs because aged mice are lacking in the expression of microglial-specific anti-inflammatory genes.

In a mouse model of systemic infection, researchers observed an increase in microglial cell count and a more pro-inflammatory environment in middle-aged infected mice. This study is consistent with previous evidence showing that inflammaging, or age-related inflammation, is naturally heightened in the nervous system. Moreover, the authors disproved their hypothesis that anti-inflammatory microglia-specific genes are responsible for the elevated inflammatory response in aged brains since the expression of anti-inflammatory mediators was elevated in middle-aged brains following infection. Thus, the cause for the increase in pro-inflammatory genes remains to be elucidated.

A common feature of neurodegenerative diseases is disruption of axonal transport, a cellular process responsible for movement of key molecules and cellular 'building blocks' including mitochondria, lipids, and proteins to and from the body of a nerve cell. Axons are long fibres that transmit electrical signals, allowing nerve cells to communicate with other nerve cells and muscles. Scientists have suggested that stimulating axonal transport by enhancing intrinsic neuronal processes in the diseased central nervous system might be a way to repair damaged nerve cells. Two candidate molecules for improving axonal function in injured nerve cells are brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB).

Researchers have now shown that delivering both of these molecules simultaneously to nerve cells using a single virus has a strong effect in stimulating axonal growth compared to delivering either molecule on its own. They tested their idea in two models of neurodegenerative disease known to be associated with reduced axonal transport, namely glaucoma and tauopathy (a degenerative disease associated with dementia).

Glaucoma is damage to the optic nerve often, but not always, associated with abnormally high pressure in the eye. In an experimental glaucoma model, the researchers used a tracer dye to show that axonal transport between the eye and brain was impaired in glaucoma. Similarly, a reduction in electrical activity in the retina in response to light suggested that vision was also impaired. The gene therapy restored axonal transport between the retina and the brain, as observed by movement of the dye. The retinas also showed an improved electrical response to light, a key prerequisite for visual restoration.

Next, the team used transgenic mice bred to model tauopathy, the build-up of 'tangles' of tau protein in the brain. Tauopathy is seen in a number of neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia. Once again, injection of the dye showed that axonal transport was impaired between the eye and the brain - and that this was restored using the viral vectors. The team also found preliminary evidence of possible improvement in the mice's short-term memory, but those results did not quite achieve statistical significance.