Fight Aging! Newsletter, April 8th 2019

Lifespan studies using C. elegans worms typically involve the deletion or silencing of a particular gene in the embryonic stage of life to see if that extends the average lifespan of affected animals. Researchers took a different approach, using small-molecule compounds to disrupt enzyme-related pathways in adult worms, in the hope that this would uncover pathways that regulate lifespan. The team used a library of about 100 such compounds, all known to inhibit enzymes called serine hydrolases in mammals. "Metabolic processes are very important in determining the rate of aging and lifespan, and serine hydrolases are major metabolic enzymes, so we thought there was a good chance we'd find an important aging-related enzyme this way."

After finding ways to get the compounds through the tough outer skin of the worms, the researchers tested them on worms that were 1 day into adulthood, and found that some of the compounds extended average worm lifespan by at least 15 percent. One, a carbamate compound called JZL184, extended worm lifespan by 45 percent at the optimal dose. More than half the worms treated with JZL184 were still alive and apparently healthy at 30 days, a time when virtually all untreated worms were dead of old age. JZL184 was originally developed as an inhibitor of the mammalian enzyme monoacylglycerol lipase (MAGL), whose normal job includes the breakdown of a molecule called 2-AG. The latter is an important neurotransmitter and is known as an endocannabinoid because it activates one of the receptors hit by the main psychoactive component in cannabis.

Curiously however, a corresponding MAGL enzyme does not exist in C. elegans worms, so JZL184's target in these animals was a mystery. Researchers found, though, that one of the main target enzymes for JZL184 in worms was fatty acid amide hydrolase 4 (FAAH-4). Although FAAH-4 and MAGL are not related in terms of their amino-acid sequences or 3-D folds, further experiments revealed, surprisingly, that FAAH-4 in worms does what MAGL does in humans and other mammals: it breaks down 2-AG. 2-AG has been linked to aging in mammals; one recent study found evidence that its levels fall in the brains of aging mice, likely due to greater MAGL activity. The results suggest, then, that studying the FAAH-4/2-AG pathway in worms could one day yield lifespan-extending strategies for humans.

Phenotypic screening has identified small-molecule modulators of aging, but the mechanism of compound action often remains opaque due to the complexities of mapping protein targets in whole organisms. Here, we combine a library of covalent inhibitors with activity-based protein profiling to coordinately discover bioactive compounds and protein targets that extend lifespan in Caenorhabditis elegans. We identify JZL184 - an inhibitor of the mammalian endocannabinoid (eCB) hydrolase monoacylglycerol lipase (MAGL or MGLL) - as a potent inducer of longevity, a result that was initially perplexing as C. elegans does not possess an MAGL ortholog.

We instead identify FAAH-4 as a principal target of JZL184 and show that this enzyme, despite lacking homology with MAGL, performs the equivalent metabolic function of degrading eCB-related monoacylglycerides in C. elegans. Small-molecule phenotypic screening thus illuminates pure pharmacological connections marking convergent metabolic functions in distantly related organisms, implicating the FAAH-4/monoacylglyceride pathway as a regulator of lifespan in C. elegans.

Exceptional longevity, defined as exceeding the average life expectancy, is multifaceted with genetic, environmental, and epigenetic factors all playing a role. Exceptionally long-lived (ELL) individuals are examples of successful ageing with a proportion demonstrating compression of morbidity. It is important to study these models of successful ageing, as these rare individuals may reveal novel longevity-associated pathways, which may ultimately translate into strategies to promote health in our ageing population.

There is evidence linking healthier cardiovascular risk profiles and lower incidence of cardiovascular disease with longevity. Analysis of lipid metabolism in longevous families identified changes in lipid concentration in the offspring of nonagenarians. Levels of apolipoproteins, important lipid transporters in the circulatory system, have been observed to decline with age. However, higher apolipoprotein levels in the exceptionally long lived have been reported, suggesting a younger apolipoprotein profile that may promote longevity.

Polygenic risk scores (PRS) for cardiovascular-related phenotypes can now be calculated due to the availability of summary data from genome-wide association studies (GWAS) examining a broad range of traits from lipids to coronary artery disease. This facilitates the evaluation of the contribution of polygenic risk for cardiovascular risk factors and disease to exceptional longevity and successful ageing. Thus, the purpose of this study was to explore the genetic profiles of ELL individuals aged (≥95 years) by assessing their polygenic risk for cardiovascular related risk and disease phenotypes relative to middle-aged controls.

This study did not confirm the hypothesis that ELL individuals have lower polygenic risk scores for cardiovascular-related phenotypes. Only the HDL cholesterol and triglyceride PRS were nominally significantly associated with ELL participants. In contrast and as expected, ELL individuals had higher polygenic risk scores for exceptional longevity (EL). In regards to the associations of the various cardiovascular PRS with EL, no findings survived correction for multiple testing. This is despite validating the utility of the lipid PRS by confirming positive associations with measured lipid levels in our sample. Interestingly, the different lipid PRS were based on GWAS that found a large number of genome-wide significant loci. ELL individuals had lower LDL and total cholesterol levels than controls in this study, but they did not differ on their respective PRS. This may suggest that environmental factors, perhaps lifestyle-related, influenced these lipid levels, which possibly promote longevity.

In contrast, the UK Biobank study observed that extreme parental longevity (defined as at least one parent who survived to the top 1% of age at death) had lower polygenic risk for several cardiovascular health measures. Namely coronary artery disease, systolic blood pressure, body mass index, high-density lipoproteins, low-density lipoproteins, and triglycerides. A similar result for HDL cholesterol and extreme parental longevity (EPL) by the UK Biobank to the current study was reported. Again, similar results were reported by the UK Biobank for LDL. However, the observed discrepancies between our analysis and the UK Biobank were most likely due to methodological differences, including the use of PRS that were based on different GWAS.

Cellular senescence is classically defined as the irreversible cell cycle arrest of somatic cells. While senescence can act as a potent antitumour mechanism, recent studies have shown that senescent cells accumulate in several tissues with age where they contribute to age-dependent tissue dysfunction and several age-related diseases. Senescent cells are thought to contribute to aging via a pro-oxidant phenotype and the secretion of a senescence-associated secretory phenotype (SASP), which is pro-inflammatory, profibrotic, and can also promote senescence in surrounding cells.

Senescence has been shown to occur in the heart during aging and contributes to the pathophysiology of a number of cardiovascular diseases, as clearance of senescent cells in aged and atherosclerotic mice using both genetic and pharmacological approaches improves vascular and myocardial function and attenuates age-dependent remodelling. However, the impact of senescent cells in myocardial infarction (MI) has not been investigated thus far. In this study, we hypothesise that senescent cells contribute to the poor prognosis and survival of aged individuals following MI. Previously we found that in addition to clearing senescent cells, navitoclax treatment reduced fibrosis and cardiomyocyte (CM) hypertrophy in aged mice and considered that these beneficial effects may help to improve outcomes in aged mice following MI. We therefore performed a more detailed longitudinal study to examine this possibility and to explore potential mechanisms.

Histological analysis was performed on a cohort of noninfarcted mice, to assess the baseline effects of navitoclax treatment. In addition to decreasing CM hypertrophy, treatment reduced markers of CM senescence, indicating clearance of senescent cells from the hearts of treated aged mice. Furthermore, we found a significant reduction in expression of profibrotic TGFβ2, which we previously identified as a key component of CM SASP. Functionally, navitoclax treatment significantly reduced the age-dependent increase in left ventricular (LV) mass but did not impact on ejection fraction (EF). Aged mice also exhibited a decrease in the percentage change in diastole versus end systole LV wall thickness, indicating an increased LV rigidity compared with young animals, which was also partly rescued by navitoclax treatment. Clinically, increased ventricle stiffness is related to fibrosis and hypertrophy during aging, is symptomatic of diastolic dysfunction and is observed in heart failure with preserved ejection fraction patients.

We observed that aged mice had significantly higher mortality rates following MI (60% over 5 weeks) compared with young mice and that this outcome was rescued by prior navitoclax treatment. In contrast to young mice, old mice show a significant reduction in EF between 1 and 4 weeks post-MI. Importantly, navitoclax was able to rescue this functional decline which may help to explain the improved survival of this group. Furthermore, expression of senescence markers p16 and p21 at 4 weeks following MI was reduced in the hearts of navitoclax-treated mice, consistent with reduction of the senescence burden.

Collectively, this study shows that pharmacological clearance of senescent cells in aging mice alleviates age-dependent myocardial remodelling and attenuates expression of profibrotic mediators. Navitoclax improved the maintenance of cardiac function following MI, ultimately increasing survival. An important limitation of this study is that our experimental strategy was not able to distinguish which senescent cell types are responsible for this effect, and it is possible that clearance of senescent cells in noncardiac organs impact on survival following MI. We have focussed our attention on CMs in this study as our earlier findings showed that, in the heart, markers of senescence accumulate primarily in CMs during aging. However, further studies using animal models where senescent cells can be cleared in a cell-type specific manner are required to formally show the contribution of senescent CMs to cardiac recovery post-MI.

The ability of molecules to pass through the membrane of mitochondria - the cellular structures that convert nutrients into energy - may determine whether or not autophagy, a cellular process that removes damaged and dysfunctional molecules and cellular components, is beneficial or detrimental to the health of an organism. As the accumulation of damaged molecules and defective proteins is considered a hallmark of aging, autophagy has been associated with increased longevity. In fact, model organisms in which gene mutations or measures such as calorie restriction lead to lifespan extension depend on autophagy for their beneficial effects. However, autophagy can also play a role in cancer, diabetes, neurodegeneration and in the ischemia/reperfusion injury caused by restricted blood flow.

Previous studies have suggested that inhibition of the mTORC2 molecular pathway, which controls several critical metabolic functions, shortens lifespan. Organisms in which mutations in mTORC2 or in the gene encoding its downstream effector protein SGK-1 have reduced lifespan also show increased autophagy. Experiments revealed that inhibition of autophagy can restore a normal lifespan in mTORC2/SGK1 mutant C. elegans roundworms. The researchers also found that SGK-1 can regulate the opening of the mitochondrial permeability transition pore (mPTP), which allows very small molecules to pass through the mitochondrial membrane. Excessive opening of the mPTP, either by inhibition of the mTORC2/SGK-1 pathway or by direct genetic stimulation, transforms autophagy from a beneficial to a detrimental function, resulting in a shortened lifespan. Overall, the results indicate that the beneficial effects of autophagy depend on low levels of mitochondrial permeability.

Since autophagy is believed to contribute to ischemic injury, the investigators looked at its potential role in ischemia/reperfusion (I/R) injury - the exacerbation of tissue damage that occurs when blood flow is restored to tissue to which it had been restricted. They found that mice in which expression of the gene for SGK-1 was knocked out in the liver were more susceptible to I/R injury of the liver than were unmutated animals. While both current and previous research has indicated that elevated autophagy and mitochondrial permeability are harmful in the early phases of reperfusion injury, autophagy may help reduce the severity of tissue damage at later stages when damaged cellular components must be cleared from the cell.

Autophagy is required in diverse paradigms of lifespan extension, leading to the prevailing notion that autophagy is beneficial for longevity. However, why autophagy is harmful in certain contexts remains unexplained. Here, we show that mitochondrial permeability defines the impact of autophagy on aging. Elevated autophagy unexpectedly shortens lifespan in C. elegans lacking serum/glucocorticoid regulated kinase-1 (sgk-1) because of increased mitochondrial permeability. In sgk-1 mutants, reducing levels of autophagy or mitochondrial permeability transition pore (mPTP) opening restores normal lifespan.

Remarkably, low mitochondrial permeability is required across all paradigms examined of autophagy-dependent lifespan extension. Genetically induced mPTP opening blocks autophagy-dependent lifespan extension resulting from caloric restriction or loss of germline stem cells. Mitochondrial permeability similarly transforms autophagy into a destructive force in mammals, as liver-specific Sgk knockout mice demonstrate marked enhancement of hepatocyte autophagy, mPTP opening, and death with ischemia/reperfusion injury. Targeting mitochondrial permeability may maximize benefits of autophagy in aging.

It was once believed that mammals were born with the entire supply of neurons they would have for a lifetime. However, over the past few decades, neuroscientists have found that at least two brain regions - the centers of the sense of smell and the hippocampus, the seat of learning and memory - grow new neurons throughout life. Researchers have now shown, in mice, that one type of stem cell that makes adult neurons is the source of this lifetime stock of new cells in the hippocampus. These findings may help neuroscientists figure out how to maintain youthful conditions for learning and memory, and repair and regenerate parts of the brain after injury and aging.

The researchers showed that the neural stem cells they found had a common molecular signature across the lifespan of the mice. They did this by labeling neural stem cells in embryos when the brain was still developing and following the cells from birth into adulthood. This approach revealed that new neural stem cells with their precursor's label were continuously making neurons throughout an animal's lifetime. This capacity is called plasticity, which is the brain's ability to form new connections throughout life to compensate for injury and disease and to adjust in response to new input from the environment. The next step for the researchers is to look for the same neural stem cells in other mammals, most importantly in humans, starting the search in post-mortem brain tissue, and to investigate how this population of neural stem cells are regulated.

Researchers have made small capsules from brown algae which hold macrophages, a type of white blood cell. Tests in mice have shown that these algae capsules may be able to increase blood flow in the limbs where tissue has been damaged. The researchers now hope to move this research into human clinical trials to help the people visiting hospital with critical limb ischaemia (CLI). Scientists have been experimenting with cells as a treatment to grow arteries in the leg for years, however, these treatments have not been effective in humans. A big challenge is that many of the cells injected into the injured area die, move away to surrounding areas, or are detected as 'foreign' by the immune system and rejected.

In this study, scientists delivered the new algae-based capsules containing macrophages to areas of injured muscle tissue in the back legs of mice. Alginate from the cell walls of brown algae, which is mainly found in cold waters in the Northern Hemisphere, was used to form the capsules. They found that these macrophages successfully remained in the injured area, new blood vessels formed, and as a result more blood reached the damaged area. Currently, to treat CLI and restore blood flow in the limbs, the blocked section of the artery has to be either bypassed during surgery or widened using a small piece of expandable mesh called a stent. However, in up to a third of patients, these methods will eventually fail or are not possible to begin with and amputation is the only option. The researchers therefore hope that this new way of delivering cells could be the key to creating an effective treatment for people suffering with CLI.

Before any physical signs or symptoms of heart failure are present, the first maladaptive changes occur in cardiac cell metabolism - how the heart fuels itself to pump blood through the body constantly. Our hearts burn fuel, much like combustion engines in cars. Instead of gasoline, our heart cells burn fats and a small amount of glucose. When our hearts become chronically stressed, they try to adapt, but some of those changes make things worse.

Researchers examined both mouse models of heart failure and human heart tissue obtained from heart failure patients before and after heart assist devices were surgically implanted. They found that the amount of a reactive fat compound, called acyl-CoA, is nearly 60 percent lower in failing hearts compared to normal hearts. This disruption in the heart's normal metabolism creates toxic fats that impair the heart's ability to function and pump properly. Then the team tested mice that overexpressed a gene for a protein called ACSL1, that's known to make acyl-CoA. When exposed to conditions that cause heart failure, the mice kept making normal amounts of acyl-CoA and the extent of heart failure was reduced and delayed.

By maintaining this fat compound, acyl-CoA, the hearts retained their ability to burn fat and generate energy. Importantly, overexpression of ACSL1 also reduced toxic fats, normalized cell function, and reduced the progressive loss of function in the enlarged mouse hearts. When the team examined failing human hearts that had the help of a left ventricular assist device (LVAD), they found similar effects - the levels of acyl-CoA had restored to normal when the sick hearts didn't have to work beyond their capacity. "This tells us there's an important relationship between fat metabolism in the heart and the inability to pump well, and we need to learn more. We believe targeting the normalization of acyl-CoA is a new approach to explore." Next, the team wants to explore how normalizing acyl-CoA helps reduce toxic fats and increase protective fats inside the heart. Soon, they hope to use advanced imaging to track fat metabolism and function in patients' hearts.

The atmosphere of the event was very much friendly and informal, with plenty of opportunities to join conversations with researchers and advocates during the breaks while having a bite or a drink. The lineup of speakers included many big names, including Mike West, Judith Campisi, Vadim Gladyshev, Jerry Shay, Nir Barzilai, Kelsey Moody, Julie Andersen, and Ruby Yanru Chen-Tsai. Everyone I asked said that the presentations were all top notch, but I can't really say anything about them, given that I spent nearly every moment of my stay running after researchers who were being pulled left and right by people who needed to meet them for whatever reason.

Even though I'd gotten used to asking people for interviews fairly quickly, it still felt funny to have breakfast every morning while Nir Barzilai was sitting with other researchers a few tables away, hearing the unmistakable voice of Aubrey de Grey as he entered the room, or knowing that I could easily bump into, say, MitoSENS lead Matthew O'Connor, as I walked around the hotel. Speaking of MitoSENS, at the end of her talk, Dr. Amutha Boominathan mentioned the upcoming MitoSENS 2 campaign on Lifespan.io, which will be aimed at testing allotopic expression in mice, providing proof of concept that the technique can work in mammals; in other SENS news, during the conference, Aubrey de Grey announced the tenth anniversary of the SENS Research Foundation, and a shiny new website was recently launched in celebration.

Personally, I think the best part of Undoing Aging 2019 was the feeling of being together with so many like-minded people who all agree that aging can and should be defeated; they may all have different reasons to want to see the end of aging, and they may even have different opinions on how and when this will be accomplished, but they're all working together, each in his or her own way, to achieve this common goal. It was heartening to see that they all agree that aging can be brought to its knees, even if they might disagree on methodologies and timeframes; their optimism is what we need to convince the public that a life without aging isn't a pipe dream anymore.

Stem cell senescence contributes to stem cell exhaustion, a major cause of physiological and pathological aging. Mesenchymal stem cells (MSCs) are adult multipotent cells in various mesodermal tissues that are capable of differentiating into mature cells such as osteoblasts, chondrocytes, and adipocytes. Both physiologically aged individuals and patients with premature aging syndromes exhibit functional degeneration in mesodermal tissues, along with exhaustion of MSC populations, thus characterized by atherosclerosis, osteoporosis, osteoarthritis, etc.

CBX4, a component of polycomb repressive complex 1 (PRC1), plays important roles in the maintenance of cell identity and organ development through gene silencing. However, whether CBX4 regulates human stem cell homeostasis remains unclear. In this study, we reported that CBX4 was downregulated during human MSC (hMSC) senescence and accordingly investigated the role of CBX4 in maintaining cellular homeostasis in hMSCs. Targeted CBX4 depletion in hMSCs resulted in loss of nucleolar heterochromatin, enhanced ribosome biogenesis, increased protein synthesis, and accelerated cellular aging. CBX4 overexpression alleviated senescent phenotypes in both physiologically and pathologically aged hMSCs.

More importantly, lentiviral vector-mediated CBX4 overexpression attenuated the development of osteoarthritis in mice. We demonstrate that CBX4 safeguards hMSCs against cellular senescence through the regulation of nucleolar architecture and function, suggesting a target for therapeutic interventions against aging-associated disorders.

Regular moderate- to vigorous-intensity physical activity (MVPA) is associated with a lower risk of cardiovascular disease; certain cancers; and premature death. In addition, the amount of time spent sedentary - distinct from physical inactivity - is associated with a higher risk of death and disease. That may be a result, at least in part, from sedentary behavior displacing physical activity.

Most previous studies have explored the potential effect of sedentary time without considering the physical activity it displaces, leaving a gap in the understanding of the issue. To explore further, investigators analyzed self-reported sitting time, light physical activity, and moderate/vigorous physical activity among 92,541 participants in the ACS's Cancer Prevention Study II Nutrition Cohort.

The analysis reviewed sedentary time and activity levels over 14 years. It found among those who were the least active at baseline (less than 17 minutes/day moderate to vigorous physical activity), replacing 30 minutes/day of sitting with light physical activity was associated with a 14% reduced risk of death, while replacement with moderate to vigorous physical activity was associated with a 45% reduced risk of death.

The investigators found similar but smaller associations among moderately active participants: replacing a half hour of sedentary time with light physical activity was associated with a 6% reduction in mortality among those who were moderately active; replacing 30 minutes of sitting time with moderate to vigorous physical activity was associated with a 17% mortality reduction in this group. However, for the most active (more than 38 minutes/day of MVPA), substitution of sitting time with light physical activity or MVPA was not associated with a reduction in mortality risk.

Researchers have long studied the link between aging and sirtuins, a class of proteins found in nearly all animals. Sirtuins, which have been shown to protect against the effects of aging, can also be stimulated by calorie restriction. In 2016 it was found that, in mice, low-calorie diets activate sirtuins in intestinal stem cells, helping the cells to proliferate. In a new study, researchers set out to investigate whether aging contributes to a decline in stem cell populations, and whether that decline could be reversed.

By comparing young (aged 3 to 5 months) and older (aged 2 years) mice, the researchers found that intestinal stem cell populations do decline with age. Furthermore, when these stem cells are removed from the mice and grown in a culture dish, they are less able to generate intestinal organoids, which mimic the structure of the intestinal lining, compared to stem cells from younger mice. The researchers also found reduced sirtuin levels in stem cells from the older mice.

Once the effects of aging were established, the researchers wanted to see if they could reverse the effects using a compound called nicotinamide riboside (NR). This compound is a precursor to NAD, a coenzyme that activates the sirtuin SIRT1. They found that after six weeks of drinking water spiked with NR, the older mice had normal levels of intestinal stem cells, and these cells were able to generate organoids as well as stem cells from younger mice could.

To determine if this stem cell boost actually has any health benefits, the researchers gave the older, NR-treated mice a compound that normally induces colitis. They found that NR protected the mice from the inflammation and tissue damage usually produced by this compound in older animals. "That has real implications for health. Just having more stem cells is all well and good, but it might not equate to anything in the real world. Knowing that the guts are actually more stress-resistant if they're NR-supplemented is pretty interesting."

Mitochondria are often referred to as the powerhouse of the cell, however, their physiological role goes well beyond that Mitochondria are highly dynamic organelles regulating their structure in line with metabolism, redox signaling, mitochondrial DNA maintenance, and apoptosis. Besides from generating adenosine triphosphate (ATP) for cellular energy, mitochondria are also deeply involved in providing intermediates for cellular signaling and proliferation. Mitochondria can alter their size and organization as a result of mitochondrial fission and fusion in response to various intracellular and extracellular signals. Fission and fusion events occur to meet metabolic demands and for the removal of damaged/dysfunction mitochondria. The role of mitochondrial fission and fusion in facilitating metabolism has been researched extensively. Fused mitochondrial networks typically engage more oxidative pathways of metabolism, whilst fragmentation as a result of stress impairs the oxidative pathway and increases cellular demand on glycolysis.

Ion channels are intimately involved in regulating mitochondrial function. The essential role of cationic hydrogen (H+) ion transfer in ATP production was noted as early as 1961. H+ ions are pumped from the mitochondrial matrix into the intermembrane space by the flow of electrons through the electron transport chain. These ions are then utilized to drive the ATPase machinery and phosphorylate ATP, thus creating energy for the cell. The movement of ions across the mitochondrial membrane is also essential in establishing membrane potential and maintaining proton (H+) flux. Ions transported across the inner membrane include potassium (K+), sodium (Na+) and calcium (Ca2+), alongside H+. The most well-studied ion channel within the mitochondrion is the voltage-dependent anion channel, VDAC, which is the primary route of metabolite and ion exchange across the outer mitochondrial membrane.

Mitochondrial channelopathies have been found in aging, affecting the K+, Ca2+, VDAC and permeability transition pore (Ca2+; PTP) channels. Mitochondrial Ca2+ cycling is impaired with aging in neurons, resulting from reduced Ca2+ channel activity and reduced recovery after synaptosomal stimulation. This reduced calcium recovery rate results in reduced mitochondrial membrane potential and delayed repolarization, causing mitochondrial dysfunction with aging. This effect has been found in the heart of 2 year old senescent rats. In terms of potassium channels, it has been shown that their density on the surface of mitochondria significantly declines with age and with metabolic syndromes in the heart sarcolemma. This has been shown to reduce tolerance to ischemia-reperfusion and increased injury in aged guinea pig and rat hearts, and also humans.

These effects have repercussions in increasing susceptibility to myocardial infarction and reducing neuronal activity in the elderly as mitochondrial K+ channels have been shown to play a neuroprotective role in neurological reperfusion injury in postnatal mouse pups. Amyloid-β plaques in Alzheimer's disease have been shown to increase intracellular calcium levels. This increase in intracellular calcium, and uptake into the mitochondria through the VDAC and calcium uniporter, has been shown to increase mitochondrial stress responses and initiate apoptosis in rat cortical neurons in vitro and hippocampal slices ex vivo. Recent studies in Parkinson's disease, have revealed that α-synuclein acts via the VDAC to promote mitochondrial toxicity of respiratory chain components in a yeast model of Parkinson's.

When you are repeatedly subjected to an unpleasant or painful situation over which you seem to have no control, there comes a point past which you simply give up on the very idea that you could possibly escape your predicament. Once you learn that you're helpless in the face of circumstances beyond your control, you could end up simply accepting what is happening to you, even when the circumstances have changed enough to offer a way out.

We find this relevant because this learned helplessness could play a role in the pro-aging trance - or, at least, what happens in people's minds because of the pro-aging trance is very much reminiscent of learned helplessness. If you're new around here and have no idea what the pro-aging trance is, it's basically one of the main drivers of irrational opposition to rejuvenation therapies; it's the groundless conviction that aging is a blessing in disguise and that the fact that people age to death is actually good, despite the overwhelming, blatant evidence that this is not the case.

Even though you don't spend your entire life with worsening eyesight, diabetes, cancer, or heart disease (to name but a few), you - like everyone else on the planet - were brought up with the notions that aging is inevitable and that one day it will kill you if nothing else does it first. You're accustomed to the thought that, as you age, you will lose your health to at least some extent, and you have an idea of what you might be like in old age - weak, hunched over, easily fatigued, and with feeble senses and, if you're unlucky, even more serious health problems. This idea is woven into every fiber of our society, arts, and institutions; even if you're not exposed directly to the ailments of aging for most of your life, you are exposed to the unpleasant thought that your clock is ticking - a clock that measures not just the time you have left but also your remaining health - and that there's no way that you could ever stop the clock.

In other words, you spend your entire life with the knowledge that your health is slowly declining, a decidedly unpleasant thing that, ultimately, you have no power to prevent. Therefore, you learn to accept it and make your peace with it, perhaps whimpering about it every now and again, but doing nothing else about it. Once the effects of aging manifest themselves in your old age, the feeling of helplessness gets even more real, as your health problems are no longer hypothetical and your doctor can essentially only help you manage your symptoms. This overall situation has much in common with the definition of learned helplessness.

The JAK/STAT signaling pathway is involved in many aging-related cellular functions. However, effects of overexpression of genes controlling JAK/STAT signal transduction on longevity of model organisms have not been studied. Here we evaluate the effect of overexpression of the unpaired 1 (upd1) gene, which encodes an activating ligand for JAK/STAT pathway, on the lifespan of Drosophila melanogaster.

Overexpression of upd1 in the intestine caused a pronounced shortening of the median lifespan by 54.1% in males and 18.9% in females, and the age of 90% mortality by 40.9% in males and 19.1% in females. In fat body and in nervous system of male flies, an induction of upd1 overexpression increased the age of 90% mortality and median lifespan, respectively. An increase in upd1 expression enhanced mRNA levels of the JAK/STAT target genes domeless and Socs36E.

Conditional overexpression of upd1 in different tissues of Drosophila induces pro-aging or pro-longevity effects in tissue-dependent manner. The effects of upd1 overexpression on lifespan are accompanied by the transcription activation of genes for the components of JAK/STAT pathway. As the JAK/STAT pathway is evolutionarily conserved it may be possible to discover compounds that fit the criteria of geroprotector. In our future work we plan to test the compounds from DrugAge and geroprotectors.org and other libraries potentially modulating upd, domeless and Socs36E on the lifespan of Drosophila and other organisms.