Fight Aging! Newsletter, April 10th 2017

It was once a fringe topic for scientists and a pseudo-religious dream for others. But research into the biology of ageing, and consequently extending the lifespan of humans and animals, has become a serious endeavour. The true promise of ageing research is that rather than tackling individual diseases one at a time, a single drug would treat all the diseases that arise in old age, at once. The idea of extending human life makes some uneasy, as preventing death seems unnatural. But this is already happening. Drugs and interventions developed over the past century that have almost doubled human life expectancy could be considered as anti-ageing. But when we talk about an anti-ageing pill, we mean one that targets the process of ageing itself. There is already a list of such drugs shown to extend the lives of lab animals. Many of these work through mimicking the effects of a near starvation diet.

Calorie restriction has for over 80 years been the most well-studied intervention known to delay ageing. The willpower required to maintain a near starvation diet for an entire lifetime is beyond most. But regular, short term calorie restriction has strong benefits for metabolic health. Animal studies show a reliable extension in lifespan during intermittent fasting. Early on, the effectiveness of restricting calories led scientists to hunt for genes that mediated these effects, but the long-term effects of restricting calories on ageing in humans have yet to be fully characterised, and such a study in humans would be difficult to perform.

Another anti-ageing strategy is one called "senolysis": that is, killing off old and damaged or "senescent" cells. These cells take up space, grow larger, and release substances that cause inflammation. When mice are genetically engineered so that it is possible to kill off senescent cells, health is drastically improved and animals live 20 to 30% longer. The hunt is now on for "senolytic" drugs, which can selectively kill off senescent cells. One company, UNITY Biotechnology, recently raised 116 million to achieve this.

The California Health and Longevity Institute (CHLI) is a combination spa, medical clinic, fitness center, and research institution founded in 2006 by David Murdock, a 93-year-old billionaire who made a fortune in real estate and later bought the Dole Foods company, and who has something of an obsession with increasing his time on this earth through the combination of science and lifestyle choices. His successors are numerous. Oracle co-founder Larry Ellison, who has said that "death never made any sense to me," has spent 430 million on anti-aging research; Google founders Sergey Brin and Larry Page launched Calico, a secretive company that's seeking to extend lifespan through genetic research and drug development. Ex-financier and philanthropist Michael Milken is funneling money toward speeding up the development of drugs and other medical treatments for the chronic diseases associated with aging, and Jeff Bezos has just invested in a company called UNITY Biotechnology that is "targeting cellular mechanisms at the root of age-related diseases."

Meanwhile, PayPal co-founder and early Facebook investor Peter Thiel's Breakout Labs funds companies trying to extend the useful life of various body parts; Thiel himself has reportedly given millions to a foundation aiming to increase the human life-span. I wondered aloud why anti-aging research is happening in such concentration around the city and why so much of it is funded with tech money. "I think there's a fundamental optimism here that doesn't exist in other places. Silicon Valley is full of the kind of people who think that being rejected 43 times is not a reflection of their likelihood of success." That's precisely the attitude required to believe that death can be forestalled, or even foiled.

At the Buck Institute 180 scientists work to develop therapies to slow aging. One of them is Judith Campisi, a cancer researcher who, years back, began studying senescent cells-cells that have stopped dividing. Initially senescence wasn't thought of as bad but rather as the alternative to cells becoming cancerous. But she started to think the people in her field had it all wrong-that senescent cells were dangerous because they were oozing yucky stuff that caused inflammation in the body. (One of the hallmarks of aging is that the body carries around more inflammation, which is a major factor in, if not the cause of, age-related diseases, including cancer and heart and liver disease.) Senescent cells, Campisi and colleagues found, were essentially polluting their neighbors, causing time's ravages. Last year Campisi helped found UNITY Biotechnology, a lifespan-enhancing biotech firm in San Francisco that had received 20 million in financing even before Jeff Bezos jumped in. "We're trying to devise ways now to tame that secretory characteristic of the cell. The other next step is to make them go away."

Renowned UK investor and entrepreneur Jim Mellon gives his keynote talk at Master Investor Show 2017. Presenting to a packed-out audience, Jim focuses on longevity as the next 'money fountain' and subject of his forthcoming book, Juvenescence. His engaging, impassionate speech also covers the latest macroeconomic developments and prospects in the U.S. and Europe, and the future trends that could provide returns for investors.

We believe that over the coming decade the life science sector will be leading one of the most meaningful periods of scientific discovery and advancement. This period of development has been underpinned by two seminal moments - the discovery of the structure of DNA and the sequencing of the human genome; the latter occurring nearly 50 years after the former. Subsequent breakthroughs stemming from the discovery of DNA will give new hope to those with certain diseases who relatively recently would have had none. These breakthroughs are coinciding with a period in which the world's population is undergoing the most ubiquitous and rapid aging in its history. This, we believe, will lead to the life science sector gaining new prominence and that the biggest successes in the sector will ultimately dwarf the likes of Apple, Exxon and BHP that are the current colossi of the stock market.

Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging.

Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1 df/df dwarfism, calorie restriction, or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.

Age-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging "clock", a robust biomarker of aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1 df/df mutation, calorie restriction, and rapamycin.

In wild-type mice fed an unsupplemented ad libitum diet, age-associated hypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function. Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age. Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histone modifications and resembled hypermethylation in liver cancer. Age-associated methylation changes are suppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically in rapamycin treated mice.

Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time.

Here, we profile genome-wide changes in DNA methylation, gene expression and lipidomics in response to DR and aging in female mouse liver. DR is generally strongly protective against age-related changes in DNA methylation. During aging with DR, DNA methylation becomes targeted to gene bodies and is associated with reduced gene expression, particularly of genes involved in lipid metabolism. The lipid profile of the livers of DR mice is correspondingly shifted towards lowered triglyceride content and shorter chain length of triglyceride-associated fatty acids, and these effects become more pronounced with age. Our results indicate that DR remodels genome-wide patterns of DNA methylation so that age-related changes are profoundly delayed, while changes at loci involved in lipid metabolism affect gene expression and the resulting lipid profile.

It may not be the most appetizing way to extend life, but researchers have shown for the first time that older fish live longer after they consumed microbes from the poo of younger fish. So-called 'young blood' experiments that join the circulatory systems of two rats - one young and the other old - have found that factors coursing through the veins of young rodents can improve the health and longevity of older animals. But the new first-of-its-kind study examined the effects of 'transplanting' gut microbiomes on longevity. It is anticipated that scientists will test whether such microbiome transplants can extend lifespan in other animals.

Life is fleeting for killifish, one of the shortest-lived vertebrates on Earth: the fish hits sexual maturity at three weeks old and dies within a few months. Previous studies have hinted at a link between the microbiome and ageing in a range of animals. As they age, humans and mice tend to lose some of the diversity in their microbiomes, developing a more uniform community of gut microbes, with once-rare and pathogenic species rising to dominance in older individuals. The same pattern holds true in killifish, whose gut microbiomes at a young age are nearly as diverse as those of mice and humans.

To test whether the changes in the microbiome had a role in ageing, researchers 'transplanted' the gut microbes from 6-week-old killifish into middle-aged 9.5-week-old fish. They first treated the middle-aged fish with antibiotics to clear out their gut flora, then placed them in a sterile aquarium containing the gut contents of young fish for 12 hours. Killifish don't usually eat faeces, but they would probe and bite at the gut contents to see whether it was food, ingesting microbes in the process. The transplanted microbes successfully recolonized the guts of the fish that received them, the team found. At 16 weeks of age, the gut microbiomes of middle-aged fish that received 'young microbes' still resembled those of 6-week-old fish.

The young microbiome 'transplant' also had dramatic effects on the longevity of fish that got them: their median lifespans were 41% longer than fish exposed to microbes from middle-aged animals, and 37% longer than fish that received no treatment (antibiotics alone also lengthened lifespan, but to a lesser extent). And at 16 weeks - old age, by killifish standards - the individuals that received young gut microbes darted around their tanks more frequently than other elderly fish, with activity levels more like 6-week-old fish. By contrast, gut microbes from older fish had no effect on the lifespans of younger fish. Exactly how microbes influence lifespan is hazy. "The challenge with all of these experiments is going to be to dissect the mechanism. I expect it will be very complex."

Gut bacteria occupy the interface between the organism and the external environment, contributing to homeostasis and disease. Yet, the causal role of the gut microbiota during host aging is largely unexplored. Here, using the African turquoise killifish (Nothobranchius furzeri), a naturally short-lived vertebrate, we show that the gut microbiota plays a key role in modulating vertebrate life span. Recolonizing the gut of middle-age individuals with bacteria from young donors resulted in life span extension and delayed behavioral decline. This intervention prevented the decrease in microbial diversity associated with host aging and maintained a young-like gut bacterial community, characterized by overrepresentation of the key genera Exiguobacterium, Planococcus, Propionigenium and Psychrobacter. Our findings demonstrate that the natural microbial gut community of young individuals can causally induce long-lasting beneficial systemic effects that lead to life span extension in a vertebrate model.

Technological breakthroughs surrounding genomic platforms have led to major insights about age related DNA methylation changes in humans. In mammals, DNA methylation represents a form of genome modification that regulates gene expression by serving as a maintainable mark whose absence marks promoters and enhancers. During development, germline DNA methylation is erased but is established anew at the time of implantation. Abnormal methylation changes that occur because of aging contribute to the functional decline of adult stem cells. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or indirectly, via additive effects, ultimately leading to transcriptional changes of the stem cells.

Several studies describe highly accurate age estimation methods based on combining the DNA methylation levels of multiple CpG dinucleotide markers. We recently developed a multi-tissue epigenetic age estimation method (known as the epigenetic clock) that combines the DNA methylation levels of 353 epigenetic markers known as CpGs. The weighted average of these 353 epigenetic markers gives rise to an estimate of tissue age (in units of years), which is referred to as "DNA methylation age" or as "epigenetic age". DNA methylation age is highly correlated with chronological age across the entire lifespan. We and others have shown that the human epigenetic clock relates to biological age (as opposed to simply being a correlate of chronological age), e.g. the DNA methylation age of blood is predictive of all-cause mortality even after adjusting for a variety of known risk factors.

Many research questions and preclinical studies of anti-aging interventions will benefit from analogous epigenetic clocks in animals. To this end we sought to develop an accurate epigenetic clock for dogs and wolves. Dogs are increasingly recognized as a valuable model for aging studies. Dogs are an attractive model in aging research because their lifespan (around 12 years) is intermediate between that of mice (2 years) and humans (80 years), thus serving as a more realistic model for human aging than most rodents. The maximum lifespan of dogs is known to correlate with the size of their breed. Based on previous studies in human, we expect that the age acceleration (difference between epigenetic age and chronological age) correlates with longevity. We hypothesize that dogs whose epigenetic age is larger than their chronological age are aging more quickly, while those with negative value are aging more slowly. Thus, we would expect to see a correlation between age acceleration and dog breed size. We also sought to build an epigenetic clock for gray wolves because alternative age estimation methods have limitations.

Our study demonstrates that DNA-methylation correlates with age in dogs and wolves as it does in human and related species. This age-dependence of DNA-methylation is conserved at syntenic sites in the respective genomes of these canid species as well for more distantly related mammalian genomes such as human. Overall, our study demonstrates that dogs age in a similar fashion to humans when it comes to DNA methylation changes. Based on our preliminary blood samples of 108 canid specimens, including both dogs and wolves, we accurately measured the methylation status of several hundred thousand CpGs. We demonstrate that these data can produce highly accurate age estimation methods (epigenetic clocks) for dogs and wolves separately. By first removing sites that were variable between dogs and wolves, we could also establish a highly accurate epigenetic clock for all canids (i.e. dogs and wolves combined). This clock allows us to estimate the age of half the canids to within a year.

Aging is a universal biological phenomenon, except perhaps in the genus Hydra, which appears to be immortal. As such, it is difficult to label aging as a disease, at least when a departure from "normality" is a criterion for a disease. The fundamental processes responsible for aging are still incompletely understood, but environment, genes and chance all play important roles. These processes can be accelerated by diseases which tend to aggregate in older persons, such as diabetes, cancer, hypertension and atherosclerosis, largely because the aged have had more time to acquire these degenerative diseases. When one attempts to define these diseases in the older person, it is frequently necessary to adjust criteria for what might be expected from chronological aging per se; for example in the detection of osteoporosis by DEXA scanning or for detection of chronic obstructive pulmonary disease by spirometry. The disentangling of the intertwined phenomena of age-related disease and physiologic aging can be difficult and challenging. As succinctly captured by Tom Kirkwood in 1999, "grasping the correct distinction between normal aging and disease smacks of a semantic quibble, but words are powerful and the consequences of how we use them can be far-reaching".

The kidneys age in a stereotypical fashion, affecting many aspects of their function, such as glomerular filtration rate (GFR). The aggregate GFR of both kidneys (wkGFR) is equal to the product of the number of functioning nephrons (NN) and the average GFR of single nephron (snGFR). Although difficult to study in humans, the investigation of values for the elements of this equation, according to healthy (physiologic) aging, has yielded some interesting findings. We are all born with a complement of nephrons determined in large part by the process of nephrogenesis in utero. Thus, one can only lose, not gain nephrons as one ages and the NN at any age is determined by NN at birth (nephron endowment) and the rate of post-natal loss of nephrons. Among 1638 living donors in a past study, an average adult 18-29 years old has about 1,008,000 glomeruli per kidney, 991,000 of which are presumably functioning and 17,000 of which have undergone a scarring process known as focal and global glomerulosclerosis (FGGS).

Thus, according to the equation above, if the wkGFR for two kidneys is 110ml/min, the average snGFR of the functioning nephrons in a healthy young adult is about 55 nl/min. By age 70-75 years the average number of glomeruli per kidney has declined to about 660,000, of which 520,400 are presumably functioning and 142,000 have undergone FGGS. If the normal wkGFR for a healthy 70-75 year old is about 75 ml/min (a loss of 35 ml/min over 5 decades), then the average snGFR is about 57 nl/min, not much different than an adult 50 years younger. Note that the absolute total number of non-sclerotic and sclerotic nephrons decrease by 35% with aging, so some nephrons must have been completely resorbed, as a consequence of atrophy and sclerosis. If these derived values represent the true state of renal physiology in the aging kidney, then healthy aging is associated with a substantial decline (35%) in total glomeruli, and an even greater number of functioning (non-sclerotic) glomeruli with aging about 48% (from 991,000 per kidney to 520,400 per kidney) over 50 years.

The mechanisms underlying this loss of nephrons with healthy aging remain uncertain, but unlike nephron loss accompanying surgical reduction of nephron mass or certain disease states associated with loss of function nephron number, the reduction of functioning nephrons in aging is not apparently accompanied by a compensatory increase in snGFR of surviving nephrons, at least not until the extremes of age have been attained. In addition, it seems that factors in addition to aging per se are responsible for the observed nephron loss other than age per se. The loss of nephrons is accompanied by interstitial fibrosis proportional to the severity of FGGS, and by tubular hypertrophy that somewhat attenuate the loss of cortical volume seen in aging kidneys.

Macrophage interactions with adipocytes are important both in states of metabolic dysfunction and in healthy adipose tissue expansion and remodeling. Despite this importance, our understanding of macrophage-adipocyte interactions is incomplete. It is known that adipose tissue macrophages transform into foam cells and drive the inflammatory changes that occur in adipose tissue, and it appears that macrophages play a protective role in adipose homeostasis, but mount a maladaptive immune response in the setting of obesity. In the setting of obesity, it has been proposed that hypertrophic adipocytes release triglycerides and nonesterified fatty acids that the macrophage can then passively internalize using standard endocytic mechanisms. However, in this study, we show that, rather than endocytosis of released lipids, the macrophages themselves actively participate in lipid liberation from the adipocyte.

Our laboratory and others have described a process in which large moieties or species tightly bound to the extracellular matrix are initially digested by macrophages in an extracellular acidic lytic compartment. We describe this process as exophagy. We have studied exophagy in the context of macrophage degradation of aggregated low-density lipoprotein (LDL), as occurs during atherogenesis. Exophagic catabolism of aggregated LDL results in uptake of cholesterol by the macrophage, leading to foam cell formation. While foam cell formation has been an area of extensive study in the atherosclerosis field, macrophage foam cell formation in adipose tissue has only been reported recently. Given the similarities between these two systems, we examined whether exophagy could be responsible for macrophage degradation of dead adipocytes. This would allow extracellular catabolism and subsequent uptake of pieces of the adipocyte, facilitating macrophage foam cell formation as a consequence of clearing dead adipocytes. Exophagy-mediated foam cell formation is a highly efficient means by which macrophages internalize large amounts of lipid, which may overwhelm the metabolic capacity of the macrophage, as has been demonstrated in the setting of atherosclerosis, leading to a maladaptive inflammatory response. This biology may have particular relevance during clearance of dramatically enlarged adipocytes, as occurs in the setting of obesity.

Here, we demonstrate that adipose tissue macrophages form an extracellular acidic hydrolytic compartment containing lysosomal enzymes delivered via exocytosis. Initial catabolism of the dead adipocyte occurs in these extracellular compartments, allowing the macrophage to internalize pieces of the adipocyte and transform it into a foam cell. We show that macrophage foam cell formation is specific to interaction with dead or dying adipocytes and is blocked when exophagy is inhibited.

Every time you throw a ball, swing a golf club, reach for a jar on a shelf, or cradle a baby, you can thank your rotator cuff. This nest of tendons connecting your arm bone to your shoulder socket is a functional marvel, but it's also prone to tearing and difficult to surgically repair. Rotator cuff problems are common, with about 2 million people afflicted and about 300,000 rotator cuff repair surgeries every year in the U.S. Surgeons have many techniques to reconnect the tendon to the bone. The problem is that often they don't stay reconnected. In a new study, researchers using a nano-textured fabric seeded with stem cells were able to get torn rotator cuff tendons to regenerate in animals. Not only did the tendons wrapped in the fabric make a better attachment to the bone, they were stronger overall, with a cell structure that looked more like natural, undamaged tissue. Tendons repaired with a purely surgical technique healed with a more disorganized cell structure, which made the tendon itself weaker and more prone to failure.

The combination of the "nano-mesh" with stem cells seems to be critical. Surgeons will sometimes inject stem cells into rotator cuff repairs, but results from this technique are mixed. Stem cells alone don't necessarily stick around at the surgery site. Adding the mesh changes that. The mesh, made of a nanostructured polymer combining polycaprolactone and polyphosphazene provides an attractive habitat for the stem cells to hunker down. Once they settle into the rotator cuff location, the stem cells begin sending out signals directing other cells to align and grow into tendon tissue. Images taken at six and 12 weeks in animals show that torn rotator cuff tissue reorganizes under the influence of the matrix and stem cells. Once the tendon is fully regenerated, the polymer matrix can dissolve. If the combo polymer mesh plus stem cell technique proves durable in human rotator cuff tendons, the researchers won't stop there. "Being able to regenerate complex soft tissues like the rotator cuff is an important step, but we have even bigger goals."

Aging is a phenomenon in which a cell's ability to divide and grow deteriorates as it gets older, and this causes degradation of the body and senile diseases. The inhibition and recovery of aging is an instinctive desire of humans; thus, it is a task and challenge of biologists to identify substances that control aging and analyze aging mechanisms. Researchers have been conducting research to reverse the aging process by shifting the existing academia's 'irreversibility of aging' paradigm. To reverse the aging process, the research team searched for factors that could control aging and tried to discover substances that could restore cell division capacity. As a result, it was confirmed that KU-60019, an inhibitor of ATM protein, which is a phosphorylation enzyme, recovers the functions of aging cells through activation of lysosomal functions and induction of cell proliferation.

The degradation of lysosomes, which are intracellular organelles responsible for autophagy and decomposition of biopolymers such as proteins and lipids in the cell, leads to cell senescence by accumulating biomolecules that must be removed in cells and causes instability of the metabolism such as removal of dysfunctional mitochondria that do not function. The research team was the world's first to confirm that as cell aging progresses, the vacuolar ATPase (v-ATPase) protein involved in the lysosomal activity regulation is phosphorylated by the ATM protein, and the binding force between the units constituting the v-ATPase is weakened, so consequently the function of lysosomes deteriorates.

In addition, the team has proven that the reversible recovery of aging is possible through its experiment that shows the regulation of ATM protein activation by KU-60019 substances induces the reduction of phosphorylation of v-ATPase, thereby inducing recovery of mitochondrial function and functional recovery of the lysosome and autophagy system as well as promoting wound healing in aging animal models.

Researchers have announced the results of an animal study evaluating the effectiveness of a naturally-occurring chemical that holds promise in anti-aging therapy. The Astaxanthin compound CDX-085 (developed by Cardax) showed the ability to significantly activate the FOXO3 gene, which plays a proven role in longevity. "All of us have the FOXO3 gene, which protects against aging in humans. But about one in three persons carry a version of the FOXO3 gene that is associated with longevity. By activating the FOXO3 gene common in all humans, we can make it act like the "longevity" version. Through this research, we have shown that Astaxanthin "activates" the FOXO3 gene." Astaxanthin is a naturally occurring compound found in seafood such as shrimp, lobster, and salmon, and is typically sourced from algae, krill, or synthesis. Multiple animal studies have demonstrated that Astaxanthin reduces inflammation, heart and liver damage, cholesterol levels, and risk of stroke. In humans, Astaxanthin also has been shown to lower inflammation and triglycerides.

For those who have a certain gene (the FOXO3 "G" genotype) there is "extra protection" against the risk of death as you get older, compared to average persons. Using data from the Kuakini Hawaiʻi Lifespan Study, a substudy of the 50-year Kuakini Honolulu Heart Program (Kuakini HHP), and the National Institute on Aging's Health, Aging and Body Composition (Health ABC) study as a replication cohort, researchers found that people with this FOXO3 gene have an impressive 10% reduced risk of dying overall and a 26% reduced risk of death from coronary heart disease over a 17 year period. Data are based on a 17-year prospective cohort study of 3,584 older American men of Japanese ancestry from the Kuakini HHP cohort study and a 17-year prospective replication study of 1,595 white and 1,056 African-American elderly individuals from the Health ABC cohort.

Researchers have discovered a possible new explanation for female infertility. Thanks to cutting-edge microscopy techniques, they observed for the first time a specific defect in the eggs of older mice. This defect may also be found in the eggs of older women. The choreography of cell division goes awry, and causes errors in the sharing of chromosomes. "We found that the microtubules that orchestrate chromosome segregation during cell division behave abnormally in older eggs. Instead of assembling a spindle in a controlled symmetrical fashion, the microtubules go in all directions. The altered movement of the microtubules apparently contributes to errors in chromosome segregation, and so represents a new explanation for age-related infertility."

Women - and other female mammals - are born with a fixed number of eggs, which remain dormant in the ovaries until the release of a single egg per menstrual cycle. But for women, fertility declines significantly at around the age of 35. "One of the main causes of female infertility is a defect in the eggs that causes them to have an abnormal number of chromosomes. These so-called aneuploid eggs become increasingly prevalent as a woman ages. This is a key reason that older women have trouble getting pregnant and having full-term pregnancies. It is also known that these defective eggs increase the risk of miscarriage and can cause Down's syndrome in full-term babies." Scientists previously believed that eggs are more likely to be aneuploid with age because the "glue" that keeps the chromosomes together works poorly in older eggs. This is known as the "cohesion-loss" hypothesis. "Our work doesn't contradict that idea, but shows the existence of another problem: defects in the microtubules, which cause defective spindles and in doing so seem to contribute to a specific type of chromosome segregation error."

Microtubules are tiny cylindrical structures that organize themselves to form a spindle. This complex biological machine gathers the chromosomes together and sorts them at the time of cell division, then sends them to the opposite poles of the daughter cells in a process called chromosome segregation. "In mice, approximately 50% of the eggs of older females have a spindle with chaotic microtubule dynamics." The researchers conducted a series of micromanipulations on the eggs of mice between the ages of 6 and 12 weeks (young) and 60-week-old mice (old). "We swapped the nuclei of the young eggs with those of the old eggs and we observed problems in the old eggs containing a young nucleus. This shows that maternal age influences the alignment of microtubules independently of the age of the chromosomes contained in the nuclei of each egg." The researchers note that spindle defects are also a problem in humans. In short, the cellular machinery works less efficiently in aged eggs, but this is not caused by the age of the chromosomes.

Researchers have created a new system to produce human T cells, the white blood cells that fight against disease-causing intruders in the body. The system could be utilized to engineer T cells to find and attack cancer cells, which means it could be an important step toward generating a readily available supply of T cells for treating many different types of cancer. The thymus sits in the front of the heart and plays a central role in the immune system. It uses blood stem cells to make T cells, which help the body fight infections and have the ability to eliminate cancer cells. However, as people age or become ill, the thymus isn't as efficient at making T cells.

T cells generated in the thymus acquire specialized molecules, called receptors, on their surface, and those receptors help T cells seek out and destroy virus-infected cells or cancer cells. Leveraging that process has emerged as a promising area of cancer research: Scientists have found that arming large numbers of T cells with specific cancer-finding receptors - a method known as adoptive T cell immunotherapy - has shown remarkable results in clinical trials. Adoptive T cell immunotherapy typically involves collecting T cells from people who have cancer, engineering them in the lab with a cancer-finding receptor and transfusing the cells back into the patient.

Since adoptive T cell immunotherapy was first used clinically in 2006, scientists have recognized that it would be more efficient to create a readily available supply of T cells from donated blood cells or from pluripotent stem cells, which can create any cell type in the body. The challenge with that strategy would be that T cells created using this approach would carry receptors that are not matched to each individual patient, which could ultimately cause the patient's body to reject the transplanted cells or could cause the T cells to target healthy tissue in addition to cancer cells.

Researchers used a new combination of ingredients to create structures called artificial thymic organoids that, like the thymus, have the ability to produce T cells from blood stem cells. The scientists found that mature T cells created in the artificial thymic organoids carried a diverse range of T cell receptors and worked similarly to the T cells that a normal thymus produces. The researchers now are looking into using the system with pluripotent stem cells, which could produce a consistent supply of cancer-fighting T cells for patients in need of immediate life-saving treatment.

Researchers have found that a compound called rapamycin has unusual properties that may help address neurologic damage such as Alzheimer's disease. The newly-discovered mechanism is what researchers say might help prevent neurologic damage and some related diseases. "The value of rapamycin is clearly linked to the issue of cellular senescence, a stage cells reach where they get old, stop proliferating and begin to secrete damaging substances that lead to inflammation. Rapamycin appears to help stop that process." This secretion of damaging compounds creates a toxic environment called senescence-associated secretory phenotype, or SASP. It's believed this disrupts the cellular microenvironment and alters the ability of adjacent cells to function properly, compromising their tissue structure and function. This broad process is ultimately linked to aging.

"The increase in cellular senescence associated with aging, and the inflammation associated with that, can help set the stage for a wide variety of degenerative disease, including cancer, heart disease, diabetes, and neurologic disease such as dementia or Alzheimer's. In laboratory animals when we clear out senescent cells, they live longer and have fewer diseases. And rapamycin can have similar effects."

Prior to this research, it had only been observed that there was one mechanism of action for rapamycin in this process. Scientists believed it helped to increase the action of Nrf2, a master regulator that can "turn on" up to 200 genes responsible for cell repair, detoxification of carcinogens, protein and lipid metabolism, antioxidant protection and other factors. In the process, it helped reduce levels of SASP. The new study concluded that rapamycin could also affect levels of SASP directly, separately from the Nrf2 pathway and in a way that would have impacts on neurons as well as other types of cells. "Any new approach to help protect neurons from damage could be valuable. Other studies, for instance, have shown that astrocyte cells that help protect neuron function and health can be damaged by SASP. This may be one of the causes of some neurologic diseases, including Alzheimer's disease."

Lots of factors can contribute to how fast an organism ages: diet, genetics and environmental interventions can all influence lifespan. But in order to understand how each factor influences aging - and which ones may help slow its progression - researchers need an accurate biomarker, a clock that distinguishes between chronological and biological age. A traditional clock can measure the passage of chronological time and chronological age, but a so-called epigenetic clock can measure biological age. Epigenetic clocks already exist to reflect the pace of aging in humans, but in order to measure and test the effects of interventions in the lab, investigators have developed an age-predicting clock designed for studies in mice. The new clock accurately predicts mouse biological age and the effects of genetic and dietary factors, giving the scientific community a new tool to better understand aging and test new interventions.

To develop their "clock," researchers took blood samples from 141 mice and, from among two million sites, pinpointed 90 sites from across the methylome that can predict biological age. (The methylome refers to all of the sites in the genome where chemical changes known as methylation take place, changing how and when DNA information is read). The team then tested the effects of interventions that are known to increase lifespan and delay aging, including calorie restriction and gene knockouts. They also used the clock to measure the biological ages of induced pluripotent stem cells (iPSCs), which resemble younger blood.

The research team hopes that their technique will be useful for researchers who are studying new aging interventions in the lab. Currently, it can take years and hundreds of thousands in funding to study mice over their lifespans and determine the effectiveness of a single intervention. Although it is no small feat to sequence the entire methylome, the new clock could allow for studies to be carried out much faster and on a larger scale. "Our hope is that researchers will be able to use this biomarker for aging to find new interventions that can extend lifespan, examine conditions that support rejuvenation and study the biology of aging and lifespan control."

The vascular system is one of the major target organs affected by aging. In order to maintain vascular integrity, vascular endothelial cells (ECs) should have self-defense systems. We previously reported that vasohibin-1 (Vash1) could be one of such systems. Vash1 was originally isolated as an angiogenesis inhibitor was preferentially expressed in ECs for negative-feedback regulation. However, our subsequent analysis revealed that Vash1 has an additional function that causes an upsurge in stress resistance of ECs by increasing the expression of superoxide dismutase 2 (SOD2) and SIRT1 in ECs. Along with this finding, we observed that the decreased expression of Vash1 promotes vascular diseases such as diabetic nephropathy and atherosclerosis. We then noticed that the expression of Vash1 in ECs is downregulated with aging due to an increase in the expression of a certain microRNA, namely, miR-22. This observation raised the question as to why nature would allow a decrease in the expression of such a valuable protein with aging.

Because of the protective role of Vash1 in the vasculature, in this present study we assumed that vash1-/- mice would have a short lifespan. However, to our surprise, vash1-/- mice lived significantly longer and looked healthier than wild-type (WT) mice. We sought the cause of this healthy longevity and found that vash1-/- mice exhibited mild insulin resistance along with reduced expression of the insulin receptor (insr), insulin receptor substrate 1 (irs-1), and insulin receptor substrate 2 (irs-2) in their white adipose tissue (WAT) but not in their liver or skeletal muscle. The expression of vash1 dominated in the WAT among those 3 organs. Importantly, vash1-/- mice did not develop diabetes even when fed a high-fat diet. These results indicate that the expression of vash1 was required for the normal insulin sensitivity of the WAT and that the target molecules for this activity were insr, irs1, and irs2. The lack of vash1 caused mild insulin resistance without the outbreak of overt diabetes and might contribute to healthy longevity.