Fight Aging! Newsletter, May 20th 2019

In a bid to unravel how and why aging occurs, a plethora of different theories of aging have surfaced over the decades. The free radical theory, which was first proposed in 1957 is one of the most well-known and longstanding theories of aging. The free radical theory suggests that mitochondria play a crucial role in aging, as they are the main source of reactive oxygen species (ROS), leading to increased mitochondrial DNA (mtDNA) mutations. Such aging-associated mtDNA mutations thus perturb mitochondrial function resulting in pathological conditions. Mitochondria, the molecular batteries of the cell, play a crucial role in regulating the energy of the cells by producing adenosine triphosphate (ATP) through oxidative phosphorylation. Their prominent role in cell homeostasis in almost all tissues thus explains its postulated widespread effects on aging.

In light of the wide-ranging effects of aging and the associated neurodegenerative diseases on mitochondrial dysfunction, negative conditioning thus surfaces as a solution to tackle the problem. Despite the fact that the mechanism of action of neurodegenerative conditions on mitochondrial dysfunction remains to be elucidated, the possible mechanisms and the potential key molecules involved have been narrowed, and could lead to new avenues for therapeutic intervention to improve mitochondrial quality and function.

Molecular evidence of mitochondrial dysfunctions opens up possibilities for targeting specific molecules or complexes for biochemical or pharmacological therapeutic interventions. Given the neuroprotective function conferred by Parkin and PINK1, their deficiencies could be targeted to restore mitochondrial function in Parkinson's disease patients. For instance, nilotinib, a c-Abl tyrosine kinase inhibitor that is able to cross the blood brain barrier, can be used to increase Parkin levels. Parkin recruitment could also be increased by upregulating mutant PINK1 activity via kinetin triphosphate, an ATP analogue. Rapamycin is well-known to specifically inhibit the mammalian target of rapamycin (mTOR), which is a master regulator of growth and metabolism. Experimental evidence has shown that rapamycin reduced mitochondrial dysfunction after cerebral ischemia and this reduction was linked to significantly upregulated mitophagy.

Recently, researchers have looked at phytochemicals, natural compounds of vegetal origin, as a potential means of therapy. This approach is perceived to be closer to 'natural' treatment since the compounds are consumed in the diet, occur at physiological concentrations, or are known as traditional medicine. Notably, resveratrol, curcumin, quercetin, and sulforaphane are phytochemicals with the ability to contribute to negative conditioning of mitochondrial dysfunction. They do so by altering mitochondrial function and processes.

Dietary energy restriction (DR) by daily calorie restriction (CR) or intermittent fasting (IF) has been shown to extend lifespan and health span in various animal models. In addition, both CR and IF protect against age-related cardiovascular diseases and neurodegenerative diseases. Under CR, reactive oxygen species (ROS) generation has been observed to decrease especially at the liver and heart mitochondrial complex I in several studies. Such finding sheds light on how decreasing ROS can reduce disease occurrence. In an attempt to elucidate the molecular mechanism involved, numerous hypotheses have been put forth to explain how CR reduces ROS. One such hypothesis is that lowering the inner mitochondrial membrane potential along with the associated proton leak, may lead to a reduction in ROS generation. Due to reduced plasma concentration of hormones like thyroxin (T4) and insulin by CR, loss of double bonds in the membrane phospholipids is induced, resulting in a decline in the unsaturation/saturation index in several animal models tested. Such reduction increases membrane resistance to peroxidation injury thus lowering oxidative damage.

While numerous unresolved questions persist about the mechanistic link between neurodegenerative diseases and mitochondrial dysfunction, the fact that mitochondrial dysfunction plays a crucial role in the pathogenesis is clear. Mitochondrial dysfunction is a wide-ranging phenomenon that is triggered by a cohort of molecules, often incurring damage via multiple pathways. Despite decades of research on neurodegenerative diseases, treatment options remain purely symptomatic due to the unknown etiology. Given the common role played by mitochondrial dysfunction in neurodegenerative conditions, it provides a potential avenue for effective therapeutic intervention, and hopefully a platform for early intervention.

The free radical theory of aging suggests that free radical-induced damage to cellular structures is a crucial event in aging; however, clinical trials on antioxidant supplementation in various populations have not successfully demonstrated an anti-aging effect. Current explanations include the lack of selectivity of available antioxidants for the various sources of oxygen radicals and the poor distribution of antioxidants to mitochondria, which are now believed to be both the primary sources of reactive oxygen species (ROS) and primary targets of ROS-induced damage. Indeed, mitochondrial dysfunction that occurs due to accumulation of oxidative damage is implicated in the pathogenesis of virtually all human age-related diseases.

Given the key role of age-dependent mitochondrial deterioration in aging, there is currently a great interest in approaches to protect mitochondria from ROS-mediated damage. Mitochondria are not only a major source of ROS but also particularly susceptible to oxidative damage. Consequently, mitochondria accumulate oxidative damage with age that contribute to mitochondrial dysfunction. Cells and even organelles possess several protection pathways against this ROS-mediated damage given that local protection is fundamental to circumvent the high reactivity of ROS. Therefore, mitochondria appear as the main victims of their own ROS production, and evidence suggests that the best mitochondrial protection will be obtained from inside mitochondria.

his conclusion has driven several potential therapeutic strategies to improve mitochondrial function in aging and pathologies. Antioxidants designed for accumulation by mitochondria in vivo have been developed and are currently being thoroughly tested for mitochondrial protection. The growing interest in ROS production associated with diseases has elicited numerous clinical trials that have also demonstrated that uncontained ROS reduction in cells is deleterious, and it appears that an adequate balance of ROS production is necessary for correct cell function. As a consequence, there is also a growing interest in the selective inhibition of ROS production of mitochondrial origin that would not affect cellular signalization involving either mitochondrial or cytosolic ROS production.

The molecule OP2113 (Anetholtrithion, or 5-(4-methoxyphenyl)dithiole-3-thione, CAS number 532-11-6) has been marketed in many countries and used in human therapy in certain countries including France, Germany, and China for its choleretic and sialogogic properties. Anetholtrithion also exhibits chemoprotective effects against cancer and various kinds of toxicity caused by some drugs and xenobiotics. These chemoprotective effects appear to be mainly due to its antioxidant properties. The most typical indications for which anetholtrithion is currently used include increasing salivary secretion in patients experiencing dry mouth.

However, until now, no precise mechanism of action has been described for this molecule. Considering the high lipophilicity of OP2113, which represents a promising characteristic for mitochondrial targeting, we investigated the effect of OP2113 on mitochondrial ROS/H2O2 production. Here we show that OP2113 decreases ROS/H2O2 production by isolated rat heart mitochondria. Interestingly, it does not act as an unspecific antioxidant molecule, but as a direct specific inhibitor of ROS production at complex I of the mitochondrial respiratory chain, without impairing electron transfer. This work represents the first demonstration of a drug authorized for use in humans that can prevent mitochondria from producing ROS/H2O2.

As we age, our brains' stem cells 'fall asleep' and become harder to wake up when repairs are needed. Despite efforts to harness these cells to treat neurological damage, scientists have until recently been unsuccessful in decoding the underlying 'sleep' mechanism. Now, researchers studying brain chemistry in mice have revealed the ebb and flow of gene expression that may wake neural stem cells from their slumber.

The team focused their attention on protein Hes1, which is strongly expressed in the adult cells. This normally suppresses the production of other proteins such as Ascl1, small amounts of which are periodically produced by active stem cells. Monitoring the production of the two proteins over time, the team pinpointed a wave-like pattern that leads to stem cells waking up and turning into neurons in the brain. When they knocked out the genetic code needed to make Hes1, the cells started to make more Ascl1, which then activated almost all the neural stem cells.

"It is key that the same genes are responsible for both the active and quiescent states of these stem cells. Only the expression dynamics differ between the two. A better understanding of the regulatory mechanisms of these different expression dynamics could allow us to switch the dormant cells on as part of a treatment for a range of neurological disorders."

Somatic stem/progenitor cells are active in embryonic tissues but quiescent in many adult tissues. The detailed mechanisms that regulate active versus quiescent stem cell states are largely unknown. In active neural stem cells, Hes1 expression oscillates and drives cyclic expression of the proneural gene Ascl1, which activates cell proliferation. Here, we found that in quiescent neural stem cells in the adult mouse brain, Hes1 levels are oscillatory, although the peaks and troughs are higher than those in active neural stem cells, causing Ascl1 expression to be continuously suppressed.

Inactivation of Hes1 and its related genes up-regulates Ascl1 expression and increases neurogenesis. This causes rapid depletion of neural stem cells and premature termination of neurogenesis. Conversely, sustained Hes1 expression represses Ascl1, inhibits neurogenesis, and maintains quiescent neural stem cells. In contrast, induction of Ascl1 oscillations activates neural stem cells and increases neurogenesis in the adult mouse brain. Thus, Ascl1 oscillations, which normally depend on Hes1 oscillations, regulate the active state, while high Hes1 expression and resultant Ascl1 suppression promote quiescence in neural stem cells.

Many older adults have a poor sense of smell, which can affect their appetite, safety, and quality of life. It is also associated with increased risk for death and may be an early sign of some diseases, like Alzheimer's disease and Parkinson's disease. Most previous studies have studied people with a poor sense of smell for relatively short periods of time, and they did not examine whether there are differences by race or sex. We also need a better understanding of the factors that might explain the relationship between poor sense of smell and increased risk for death.

Researchers analyzed data on the members of an ongoing study that was done in 2 communities in the United States (Memphis, Tennessee, and Pittsburgh, Pennsylvania). There were 2289 adults, aged 71 to 82 years, at baseline. The participants completed a Brief Smell Identification Test (BSIT). As part of the test, they smelled 12 common odors and were asked to identify each odor from 1 of 4 options. Each correct response was given a point. Using the BSIT scores, the researchers classified the participants as having good, moderate, or poor sense of smell. Participants attended several clinical study visits, where they were examined and had cognitive tests. In these visits, patients were identified as having dementia or Parkinson's disease, and staff measured participants' body weights. The main end points for the study were death from any cause; death from dementia or Parkinson's disease; and death from cardiovascular disease, cancer, or respiratory causes.

A poor sense of smell was associated with older age, male sex, black race, alcohol drinking, and smoking. It was also associated with dementia, Parkinson's disease, and chronic kidney disease. Participants with a poor sense of smell had a nearly 50% higher risk for death at 10 years. A poor sense of smell was also associated with increased risk for death from dementia or Parkinson's disease and death from cardiovascular disease. The investigators did some exploratory statistical analyses and found that weight loss and a history of dementia or Parkinson's disease could explain only part of the relationship between poor sense of smell and death.

To assess poor olfaction in relation to mortality in older adults and to investigate potential explanations, 2289 adults aged 71 to 82 years at baseline underwent the Brief Smell Identification Test in 1999 or 2000 (baseline). All-cause and cause-specific mortality was assessed at 3, 5, 10, and 13 years after baseline. During follow-up, 1211 participants died by year 13. Compared with participants with good olfaction, those with poor olfaction had a 46% higher cumulative risk for death at year 10 and a 30% higher risk at year 13.

However, the association was evident among participants who reported excellent to good health at baseline but not among those who reported fair to poor health. In analyses of cause-specific mortality, poor olfaction was associated with higher mortality from neurodegenerative and cardiovascular diseases. Mediation analyses showed that neurodegenerative diseases explained 22% and weight loss explained 6% of the higher 10-year mortality among participants with poor olfaction.

How does α-synuclein pathology spread? Researchers say immune cells bear some of the blame. Certain types of inflammation in the intestine modulate α-synuclein accumulation there. In mice, experimental colitis at a young age accelerated α-synuclein pathology in the brain 18 months later, consistent with the idea that misfolded protein can travel from gut to brain. Other research implicates brain immune cells in propagation. Mutant α-synuclein oligomers that were incapable of forming fibrils still stimulated aggregation in brain. They appeared to work their mischief by firing up inflammation, suggesting that microglia somehow mediate α-synuclein spread.

First, peripheral immunity. Scientists know that intestinal infections or inflammation can pump up α-synuclein production in the gut, perhaps as part of an antimicrobial defense. This strengthened the idea that Parkinson's disease might start in the intestine and travel from there to the brain. People who suffer from inflammatory bowel disorders are at elevated risk of Parkinson's disease, and genetic studies have found shared risk between the two. While the links are suggestive, no one had yet shown directly that gut inflammation triggered brain pathology.

Researchers provoked colitis in 3-month-old transgenic α-synuclein mice by adding dextran sulfate sodium (DSS) to their water. This irritant caused macrophages to invade the lining of the gut wall. In response, enteric neurons lying just below the mucosa, in the submucosal plexus, began to accumulate α-synuclein. The researchers aged the mice to 12 or 21 months. At 12 months, they saw no difference between the brains of control transgenics and those that had colitis as youngsters. By 21 months, however, the colitis group had six times more α-synuclein aggregates in brainstem regions than controls did. These mice had but half as many dopaminergic neurons as controls, suggestive of neurodegeneration.

Researchers are also interested in how α-synuclein aggregates propagate within the brain. When researchers injected aggregated material into mouse brain, it was quickly cleared to undetectable levels. Then, after an incubation period, aggregates appeared and spread through brain. The leading theory holds that this occurs through templated seeding of endogenous α-synuclein by the injected aggregates. To test this idea, researchers used a mutant form of α-synuclein, V40G, that forms unstructured oligomers but is incapable of forming fibrils. In a test tube, V40G blocks fibrillization of wild-type α-synuclein as well. Thus, this form should prevent templated seeding in vivo.

The researchers injected either V40G or wild-type α-synuclein into the striata of wild-type mice. To their surprise, V40G seeded aggregates even better than wild-type α-synuclein did. Four weeks after injection, mice that had received V40G had far more α-synuclein pathology in the rhinal cortex than did mice treated with wild-type protein. Why might this be? The researchers analyzed gene expression in injected brains to glean clues. They found heightened inflammatory and innate immune responses in V40G-treated animals relative to those treated with wild-type α-synuclein. Supporting this, levels of the inflammatory cytokine IL-1β shot up in numerous brain regions after V40G administration, and this spike preceded the spread of α-synuclein aggregates to these regions. Treating mice with the anti-inflammatory drug lenalidomide along with V40G prevented this spike in IL-1β.

Based on these findings, researchers proposed a new model of α-synuclein propagation. Perhaps α-synuclein oligomers kick off microglial activation and cytokine release, and this inflammatory microenvironment then aggravates nearby neurons, causing α-synuclein to clump up in their cell bodies. By this logic, rather than α-synuclein aggregates passing directly from neuron to neuron, microglia would be essentially the conveyor belt for α-synuclein pathology.

To hear Nathanial David tell it, the osteoarthritis drug his Unity Biotechnology began testing in human subjects last fall is about far more than just helping aging weekend warriors regrow cartilage in their damaged knees. It's the first step toward making us all feel young again. David, was explaining the science behind UBX0101, the drug Unity has in late phase 1 clinical trials to treat the intractable arthritic condition, which affects 14 million Americans. The company is expected to release early results within the next several weeks.

The potential payoff from the company's arthritis drug ensures investors are watching carefully. After collecting 222 million in venture capital from Jeff Bezos, Peter Thiel, Fidelity, and others on the strength of its preclinical studies, Unity went public last May, raising 85 million in an initial public offering that valued the biotech at 700 million. In 2017 researchers funded by Unity demonstrating that removing senescent cells from the injured knees of mice using UBX0101 not only reduced pain, but also prompted the joint to regrow cartilage. The scientists later repeated the finding using human knee tissue removed from patients who'd undergone total joint replacements.

Last fall doctors began injecting UBX0101 into the knees of older human patients suffering from moderate to severe osteoarthritis. Unity's selection of osteoarthritis of the knee as its first target allows the team to administer the drug locally in the joint and closely monitor how it affects the aged cells around it. Unity announced earlier this year that it's also seeking FDA approval to begin human testing for a second locally administered drug, UBX1967, that would target age-related eye diseases.

Myocardial infarction, more commonly known as a heart attack, caused by the sudden blocking of one of the cardiac coronary arteries, is the main cause of heart failure. At present, when a patient survives a heart attack, they are left with permanent structural damage to their heart through the formation of a scar, which can lead to heart failure in the future. This is in contrast to zebrafish and salamanders, which can regenerate the heart throughout life. In a new study, the team of investigators delivered a small piece of genetic material, called microRNA-199, to the heart of pigs, after a myocardial infarction which resulted in the almost complete recovery of cardiac function at one month later.

This is the first demonstration that cardiac regeneration can be achieved by administering an effective genetic drug that stimulates cardiac regeneration in a large animal, with heart anatomy and physiology like that of humans. "It is a very exciting moment for the field. After so many unsuccessful attempts at regenerating the heart using stem cells, which all have failed so far, for the first time we see real cardiac repair in a large animal. It will take some time before we can proceed to clinical trials. We still need to learn how to administer the RNA as a synthetic molecule in large animals and then in patients, but we already know this works well in mice."

Medawar's mutation accumulation hypothesis explains aging by the declining force of natural selection with age: Slightly deleterious germline mutations expressed in old age can drift to fixation and thereby lead to aging-related phenotypes. Although widely cited, empirical evidence for this hypothesis has remained limited. Here, we test one of its predictions that genes relatively highly expressed in old adults should be under weaker purifying selection than genes relatively highly expressed in young adults.

Combining 66 transcriptome datasets (including 16 tissues from five mammalian species) with sequence conservation estimates across mammals, here we report that the overall conservation level of expressed genes is lower at old age compared to young adulthood. This age-related decrease in transcriptome conservation (ADICT) is systematically observed in diverse mammalian tissues, including the brain, liver, lung, and artery, but not in others, most notably in the muscle and heart. Where observed, ADICT is driven partly by poorly conserved genes being up-regulated during aging. In general, the more often a gene is found up-regulated with age among tissues and species, the lower its evolutionary conservation. Poorly conserved and up-regulated genes have overlapping functional properties that include responses to age-associated tissue damage, such as apoptosis and inflammation. Meanwhile, these genes do not appear to be under positive selection.

Hence, genes contributing to old age phenotypes are found to harbor an excess of slightly deleterious alleles, at least in certain tissues. This supports the notion that genetic drift shapes aging in multicellular organisms, consistent with Medawar's mutation accumulation hypothesis.

Living a long and healthy life is among the most highly valued and universal human goals, so the unparalleled longevity gains recorded all over the world during the last few decades are cause for celebration. While a huge body of scholarship has shed considerable light on the 'efficiency part' of the process (i.e., the global, regional and national trajectories in life expectancy over time are very well documented), much less is known about the 'equality part'. Since mortality can arguably be considered the ultimate measure of health, lifespan inequalities should be seen as the most fundamental manifestations of health disparities.

Studies on lifespan disparities usually focus their attention on differences occurring either between or within countries. The former approach typically compares the average health performance among a cross-section of countries (most often by comparing the corresponding life expectancies) and aims at understanding why population health is better in some countries than in others. In contrast, the latter approach explores the lifespan differences that might exist among the individuals within a given country. Surprisingly, the study of global lifespan inequality - that is, the study of variations in individuals' lifespan both within and between all world countries - is largely underdeveloped.

Our findings indicate that (i) there has been a sustained decline in overall lifespan inequality, (ii) adult lifespan variability has also declined, but some plateaus and trend reversals have been identified, and (iii) lifespan inequality among the elderly has increased virtually everywhere. All these changes have occurred against a backdrop of generalized mortality reductions. While such an increase in elderly lifespan inequality should be expected in the context of increasing longevity, it is nonetheless important to document which countries or regions are spearheading the process and which ones are lagging behind.

The increase in lifespan variability among the elderly was previously investigated in a selected group of highly industrialized countries. According to the authors of that study, the systematic increases in longevity alter the health profile of survivors in fundamental ways: advances in medicine, socioeconomic conditions, and public health planning have facilitated frailer individuals reaching more advanced ages, thus increasing the heterogeneity in health profiles among the elderly. As shown in this paper, it turns out that such mechanisms might have been operating not only in high-income settings but also across all world countries and regions, irrespective of their stage in the demographic or epidemiological transitions.

Decomposing global lifespan inequality levels into within- and between-country components, we observe that most of the world variability in ages at death can be explained by differences occurring within countries. Depending on the inequality measure and the period we choose, the within-country component explains approximately 85% and 95% of the total variation. This suggests that traditional narratives in global health disparities focusing on international variations in life expectancy neglect the major source of lifespan inequality: the source that takes place within countries. This is precisely the component that has experienced the most dramatic changes during the last six decades. Indeed, our counterfactual analyses suggest that the observed changes in global lifespan inequality can be largely attributable to the changes in within-country lifespan distributions, while the contributions of increasing longevity and differential population growth have played a relatively minor role.

Since most lifespan variability takes place within countries, focusing on the trends of central longevity indicators alone disregards the major source of variability, thus potentially arriving at overly simplistic conclusions. During recent decades, much progress has been made in increasing longevity while reducing age-at-death variability across the full lifespan and, to a lesser extent, across adult ages. However, we now appear to face a new challenge: the emergence of diverging trends in lifespan inequality among the elderly around the globe. While lifespan inequality is increasing among the elderly across virtually all world countries, longevity and heterogeneity in mortality among the old has increased faster in the richer regions of the globe.

Some risk factors for osteoporosis such as being older and female or having a family history of the condition cannot be avoided. But others can, like smoking cigarettes, consuming alcohol, taking certain medications, or being exposed to environmental pollutants. But until now researchers haven't gained a firm picture of how these exposures link up with bone loss. A new study reveals a mechanism by which these factors and osteoporosis may be linked. Damage to mitochondria - key cellular organelles and energy generators - leads to a surge in the creation of cells called osteoclasts, which are responsible for breaking down bone.

The scientists took a close look at how problems with mitochondria affected a type of immune cell known as macrophages. Macrophages are a front line for the immune system, engulfing and digesting foreign invaders to the body. But macrophages can also diversify, transforming into osteoclasts when the circumstances are right. To understand how mitochondrial damage could be linked to osteoporosis through the work of macrophages, the researchers induced damage to a key enzyme responsible for energy production in mitochondria, cytochrome oxidase C, in lab-grown mouse macrophages. Doing so led the macrophages to release a variety of signaling molecules associated with an inflammatory reaction and also seemed to encourage them to go down the path toward becoming osteoclasts.

Looking closely at what was going on, they observed an anomaly with a key molecule, RANK-L, that helps regulate the bone-rebuilding process and is released by bone-building cells as a means of inducing bone break-down. When mitochondria were damaged, they underwent stress signaling and transformed into osteoclasts at a much faster rate, even when RANK-L levels were low. These osteoclasts led to greater rates of bone resorption, or break down. The researchers confirmed their findings in a mouse model, showing that animals with a mutation that leads to dysfunctional mitochondria had increased production of osteoclasts. Because some of the same environmental risk factors that seem to promote osteoporosis, like smoking and some pharmaceuticals, can also impact mitochondrial function, the team posits that this stress signaling might be the pathway by which they are acting to affect bone health.

Back in 2015, the Church lab at Harvard began testing a variety of therapies focused on age reversal using CRISPR, a gene editing system that was much easier and faster to use than older techniques. Since then, Professor Church and his lab have conducted a myriad of experiments and gathered lots of data with which to plan future strategies for tackling aging. Last year, we learned that Rejuvenate Bio had already conducted some initial studies with beagles and were planning to reverse aging using CRISPR gene therapy. The goal was to move these studies forward to a larger scale as a step towards bringing similar therapies to humans to prevent age-related diseases.

Choosing to develop therapies for dogs helps pave the way for therapies that address the aging processes in humans and could support their approval, which would otherwise be much more challenging. If Rejuvenate Bio can produce robust data in dogs showing that some processes of aging have been reversed, it lends considerable justification for human trials. The company is also taking a different tack; instead of focusing on increasing lifespan, it is instead targeting an age-related disease. Rejuvenate Bio will be launching a gene therapy trial in dogs during the fall this year to combat mitral valve disease (MVD), a condition commonly encountered in the Cavalier King Charles Spaniel breed and directly caused by the aging processes. The study will initially focus on this particular breed and expand to include other dogs with MVD as time passes.

This gene therapy is focused on adding a new piece of DNA into the cells of the dogs in order to halt the buildup of fibrotic scar tissue in the heart, which is linked to the progression of MVD and other forms of heart failure. Fibrotic tissue is the result of imperfect repair, which occurs when a more complete repair is not possible due to a lack of replacement cells or high levels of inflammation. The therapy may also be useful for other heart conditions, such as dilated cardiomyopathy (DCM). If the initial results are successful, we could see more dog breeds included as well as other conditions, including DCM, added to the program.

Mitonuclear communication is at the heart of metabolic regulation, especially in fundamental processes such as cellular respiration. All endothermic organisms have evolved high metabolic rates for increased heat production. However, birds and mammals evolved endothermy independently of each other, and demonstrate some stark differences. Birds live significantly longer lives compared with mammals of similar body size, despite having higher metabolic rates, body temperatures, and blood glucose concentration.

The underlying physiological mechanisms that explain differences between mammals and birds are varied, and include differences at tissue- and cell-levels. For both of these groups, mass-specific basal metabolic rate (BMR) decreases with body size and body size accounts for much of the variation in BMR, however, much variation among species still remains to be explained. Because BMR is defined fundamentally as the sum of tissue metabolic rates, it follows that variation in BMR may relate to the relative size of central organs.

Alternatively, cellular machinery of the tissues of birds and mammals may differ. Metabolic intensity of tissues is thought to vary because of differences in numbers of mitochondria within cells, concentrations of metabolic enzymes, activity or quantity of the membrane sodium-potassium ATPase pump, and the number of double bonds in fatty acids of cell membranes. Because of differences in whole-organism metabolic rate, we may also expect differences within the rates of cellular processes, including oxidative stress.

Oxidative stress is a balance, inherent to all aerobic organisms, between the potential damage that could be accrued by reactive oxygen species (ROS) and the resources cells have to thwart that damage through the antioxidant system. This process has gained momentum in the ecological physiology literature because it has been implicated in determining rates of aging. Here, we sought to quantify parts of the oxidative stress system in a diverse group of birds and mammals. Our question was two-fold: does oxidative stress (a product of aerobic respiration and thus BMR) scale with body mass in these two groups? And are there differences in oxidative stress between birds and mammals?

Our first finding is that cellular metabolism and every parameter that we measured to quantify oxidative stress in birds and mammals does not scale with body mass. This implies that differences at the cellular level might make small contributions to scaling at the organ level, pointing to the fact that scaling of metabolism may reside in higher levels of organization. An obvious explanation may be that organ sizes between similarly-sized birds and mammals may be disproportionally larger in birds compared with mammals, leading to higher BMR.

Secondly, birds showed significantly lower basal cellular oxygen consumption, lipid oxidative damage, and lower activities of catalase. These results together imply several possible physiological mechanisms, none of which are mutually exclusive: (i) birds may have cells with significantly fewer mitochondria or with mitochondria that are more uncoupled; (ii) birds may be less burdened by ROS production compared with mammals; or (iii) birds may have membranes with lower membrane polyunsaturation compared with mammals.

Aging is related to disruption of tissue homeostasis, which increases the risks of developing inflammatory bowel diseases (IBDs), and colon cancer. However, the molecular mechanisms underlying this process are largely unknown. Various age-related dysfunctions of adult tissue-resident stem/progenitor cells (TSCs, also known as somatic stem cells) are associated with perturbation of tissue homeostasis. Restoration of stem cell functions has attracted much attention as a promising therapeutic strategy for geriatric diseases.

The intestinal epithelium is one of the most rapidly renewing tissues in the body. Lgr5-expressing intestinal stem cells (ISCs) in crypts differentiate into epithelial cells and thereby maintain intestinal homeostasis. Therefore, dysfunction of ISCs may be important for the disruption of intestinal homeostasis and subsequent induction of functional disorders. However, the influence of aging on the functions of ISCs and induction of diseases is largely unknown.

Recent studies demonstrated that accumulation of senescent cells promotes organismal aging. Cells become senescent in response to various aging stresses, such as oxidative stress, telomere shortening, inflammation, irradiation, exposure to chemicals, and the mitotic stress, all of which induce DNA damage. Numerous types of DNA damage occur naturally and are removed by the DNA damage response (DDR). This response induces DNA repair and apoptosis; therefore, its dysregulation leads to accumulation of damaged DNA and consequently cellular dysfunctions, including tumorigenesis. The mutation rate is highest in the small and large intestines. However, the influence of aging on the DDR in ISCs has not been studied.

Here, we compared induction of the DDR, inflammation, and mitochondrial biogenesis upon irradiation between young and old mouse ISCs in vivo. Induction of the DDR and expression of associated proteins were decreased in old ISCs. The DDR was sustained in old differentiated cells, suggesting that only the responsiveness to DNA damage was perturbed and DDR capacity was potentially sustained in old ISCs. Our results suggest that the competence of the DDR in ISCs declines with age in vivo.

For over 100 years, scientists have sought to understand what links a person's general intelligence, health and aging. In a new study, scientists suggest a model where mitochondria, or small energy producing parts of cells, could form the basis of this link. This insight could provide valuable information to researchers studying various genetic and environmental influences and alternative therapies for age-related diseases, such as Alzheimer's disease. "There are a lot of hypotheses on what this link is, but no model to link them all together. Mitochondria produce cellular energy in the human body, and energy availability is the lowest common denominator needed for the functioning of all biological systems. My model shows mitochondrial function might help explain the link between general intelligence, health, and aging."

The insight came while working on a way to better understand gender-specific vulnerabilities related to language and spatial abilities with certain prenatal and other stressors, which may also involve mitochondrial functioning. Mitochondria produce ATP, or cellular energy. They also respond to their environment, so habits such as regular exercise and a diet with fruits and vegetables can promote healthy mitochondria. "These systems are being used over and over again, and eventually their heavy use results in gradual decline. Knowing this, we can help explain the parallel changes in cognition and health associated with aging. Also with good mitochondrial function, the aging processes will occur much more slowly. Mitochondria have been relatively overlooked in the past, but are now considered to relate to psychiatric health and neurological diseases. Chronic stress can also damage mitochondria and that can affect the whole body - such as the brain and the heart - simultaneously."

The mitochondrial free radical theory of aging (mFRTA) proposes that accumulation of oxidative damage to macromolecules in mitochondria is a causative mechanism for aging. Accumulation of mitochondrial DNA (mtDNA) damage may be of particular interest in this context. While there is evidence for age-dependent accumulation of mtDNA damage, there have been only a limited number of investigations into mtDNA damage as a determinant of longevity. This lack of quantitative data regarding mtDNA damage is predominantly due to a lack of reliable assays to measure mtDNA damage.

Here, we report adaptation of a quantitative real-time polymerase chain reaction (qRT-PCR) assay for the detection of sequence-specific mtDNA damage in C. elegans and apply this method to investigate the role of mtDNA damage in the aging of nematodes. We compare damage levels in old and young animals and also between wild-type animals and long-lived mutant strains or strains with modifications in reactive oxygen species detoxification or production rates. We confirm an age-dependent increase in mtDNA damage levels in C. elegans but found that there is no simple relationship between mtDNA damage and lifespan.

In order to more directly test the relevance of mtDNA damage in the context of lifespan determination, we introduce damage to mtDNA directly by exposing young C. elegans to UV- or γ-radiation. Sufficiently high levels of UV-radiation cause extensive mtDNA damage and this indeed shortened C. elegans lifespan. However, we found that lower levels of this stressor still significantly increase mtDNA damage but without causing significant detriments and that some levels even resulted in lifespan extension and healthspan improvements.

This is consistent with the concept of hormesis; that exposure to mild stress, through evoking adaptive responses and strengthening stress defense mechanisms can lead to lifespan extension. However, it is worth noting that in our experiments, even under conditions where UV damage results in hormetic benefits, damage remained detectably elevated, even on the day following exposure. The lack of evidence for a tight relationship between mtDNA damage burden and lifespan in C. elegans is consistent with our recent finding that, most likely due to the short lifespan of nematodes, mtDNA deletion do not accumulate with age in C. elegans.