Fight Aging! Newsletter, September 4th 2017

Lifespan.io is launching a crowdfunding campaign to support MouseAGE, an application to assess visual biomarkers of aging in laboratory animals. This Artificial Intelligence-powered research tool, which is being developed by Youth Laboratories, will help scientists accurately determine the biological age of mice during experiments using advanced visual recognition and machine learning techniques. The project will help speed up research on rejuvenation therapeutics while collecting useful data in a more humane way.

When we are looking at other people, we can easily determine their ages and even get a rough idea of their health by looking at their skin tone, pigmentation and elasticity, their hair color, and their other characteristics. However, the human eye cannot accurately determine subtle changes in the appearance of such tiny animals as mice, and this is where MouseAGE can help. To rapidly collect data, commercial mouse breeders, research labs, and application beta testers all over the world will take and upload many mouse photos to the database. By using machine learning combined with visual recognition, MouseAGE will learn to recognize mice from images, to define their body parts, and finally to detect the subtle visual biomarkers of aging.

If successfully funded, the MouseAGE image collection tool will be available as a free mobile application by mid-October 2017. This will allow breeding houses and research institutions to begin collecting images and send them to the database. The project team hopes to collect enough data by February 2018 and will implement the algorithm for mouse age prediction by April 2018. This biomarker system will be made available as a free application shortly afterwards.

Here at MouseAGE we are aiming to create an artificial intelligence-powered research tool to help scientists accurately determine the biological age of mice and test longevity interventions based on photographic images of mice. This will introduce the first visual biomarker for aging in mice, and will help validate potential anti-aging interventions, save animal lives, and greatly speed up the pace of longevity research. By using machine learning combined with visual recognition, MouseAGE will learn to recognize mice from images, to define their body parts, and finally to detect the subtle visual biomarkers of aging.

We have chosen to start with the C57BL/6 (the black 6) mouse strain. This is the most common lab mouse globally, so it makes sense to begin here. Collected images at this stage will total approximately 10,000, including a wide age range of the black 6 mouse - this estimate based on our earlier experience with human faces. Once we have enough photographic material, artificial intelligence training will begin.

Our primary goal is to develop the MouseAGE system so that researchers can benefit from it. This will be an application that can be installed on a personal smartphone to make, annotate, and upload images to our cloud-based system for analysis, as well as be able to perform age assessment on newly taken images. The cost includes this data collection tool for researchers, mouse recognition software and the creation of an accurate, deep-learned, mouse age assessment algorithm. This will utilize feature extraction techniques to identify visual biomarkers of mouse aging, which we want to have thoroughly tested and made available for widespread use in common lab practice.

"In previous studies, we found that osteocalcin plays multiple roles in the body, including a role in memory. We also observed that the hormone declines precipitously in humans during early adulthood. That raised an important question: Could memory loss be reversed by restoring this hormone back to youthful levels? The answer, at least in mice, is yes, suggesting that we've opened a new avenue of research into the regulation of behavior by peripheral hormones."

Researchers conducted several experiments to evaluate osteocalcin's role in age-related memory loss. In one experiment, aged mice were given continuous infusions of osteocalcin over a two-month period. The infusions greatly improved the animals' performance on two different memory tests, reaching levels seen only in young mice. The same improvements were seen when blood plasma from young mice, which is rich in osteocalcin, was injected into aged mice. In contrast, there was no memory improvement when plasma from young mice engineered to be osteocalcin-deficient was given to aged mice. But adding osteocalcin to this plasma before injecting it into the aged mice resulted in memory improvement. The researchers also used anti-osteocalcin antibodies to deplete the hormone from the plasma of young mice, reducing their performance on memory tests.

The researchers then determined that osteocalcin binds to a receptor called Gpr158 that is abundant in neurons of the CA3 region of the hippocampus, the brain's memory center. This was confirmed by inactivating hippocampal Gpr158 in mice and subsequently giving them infusions of osteocalcin, which failed to improve their performance on memory tests. The researchers did not observe any toxic effects from giving the mice osteocalcin. "It's a natural part of our body, so it should be safe. But of course, we need to do more research to translate our findings into clinical use for humans."

That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether OCN is also sufficient to improve these behaviors in wild-type mice, when circulating levels of OCN decline as they do with age. Here we show that the presence of OCN is necessary for the beneficial influence of plasma from young mice when injected into older mice on memory and that peripheral delivery of OCN is sufficient to improve memory and decrease anxiety-like behaviors in 16-month-old mice.

A second question is to identify a receptor transducing OCN signal in neurons. Genetic, electrophysiological, molecular, and behavioral assays identify Gpr158, an orphan G protein-coupled receptor expressed in neurons of the CA3 region of the hippocampus, as transducing OCN's regulation of hippocampal-dependent memory in part through inositol 1,4,5-trisphosphate and brain-derived neurotrophic factor. These results indicate that exogenous OCN can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes.

Growing evidence from recent animal and human studies suggests that T cells contribute to the development of hypertension. Previously, we demonstrated that hypertensive patients have an increased frequency of replicative senescent CD8+ T cells in peripheral blood; these cells are characterized by the loss of CD28 and the acquisition of CD57 on their surface. CD28 loss in T cells is one of the most prominent changes associated with aging in humans and is caused by the repetitive antigenic stimulation of T cells. CD57 expression is known to occur during the late stage of T-cell differentiation and might be a distinct measure of replicative senescence in T cells. Compared with CD28+ or CD57- T cells, CD28null or CD57+ T cells produce more proinflammatory cytokines and exert greater cytotoxicity. These senescent T cells are known to be associated with various inflammatory diseases in humans including cardiovascular disease.

It has been also known that cytomegalovirus infection is involved in the accumulation of CD28null or CD57+ senescent T cells. In humans, cytomegalovirus is known to be one of the most important antigens for repetitive T-cell stimulation, and latent infection with cytomegalovirus has been shown to strongly exert age-associated changes on peripheral T cell homeostasis. The cytomegalovirus-seropositive population has a higher frequency of CD28null or CD57+, replicative senescent T cells than the cytomegalovirus-seronegative population. Moreover, cytomegalovirus infection is associated with a variety of chronic inflammatory processes in cardiovascular disease such as hypertension. However, it has not been elucidated how cytomegalovirus infection and senescent T cells contribute to the pathogenesis of cardiovascular disease.

Increased arterial stiffness is one of the major mechanisms underlying the pathogenesis of hypertension. Arterial stiffness is increased in the presence of conventional cardiovascular risk factors including aging. The degree of arterial stiffness is known to be associated with various markers of inflammation, suggesting that immune responses likely play a role in increasing arterial stiffness. Therefore, we investigated whether T-cell senescence is associated with arterial stiffness in the general population, as assessed using pulse wave velocity (PWV) measurements. Next, considering the antigen reactivity of senescent T cells, we examined cytomegalovirus-specific T-cell response and analyzed the relationship between these results and the degree of arterial stiffness.

The study population consisted of 415 Koreans who were recruited from subjects initially registered in the Yonsei Cardiovascular Genome cohort. Our findings demonstrate that the frequency of senescent CD8+CD57+ T cells in peripheral blood is independently correlated with arterial stiffness. Cytomegalovirus-specific T-cell responses were analyzed because cytomegalovirus is a major driving antigen for replicative senescence in T cells. We found that cytomegalovirus-specific CD8+ T cells were more frequently observed in the CD57+ population, and cytomegalovirus-specific cytokine secretion and the cytotoxic degranulation of CD8+ T cells were independently associated with PWV. These data suggest that immune aging, especially T-cell senescence that is linked to cytomegalovirus infection, might play a role in the progression of vascular aging.

Soon to be 50, the respected head of an Australian medical institute is contemplating the latest offering from the anti-ageing industry. It's a product that tops up the levels of nicotinamide adenine dinucleotide (NAD+), a commonplace chemical made by our bodies that is crucial for our metabolism. He's not alone. Leonard Guarente has been taking NAD+ boosters for years; and in 2015 started a company, Elysium, to market them. There are likely thousands of users by now. Something has changed in the anti-ageing field. Eccentrics and gullible-types have always availed themselves of anti-ageing remedies. Dubious supplements feed a mushrooming 30 billion industry. But when evidence-clamouring scientists start popping a pill, you sit up and take notice. Like the soon-to-be-50 Australian professor, most aren't aiming to extend their lifespan; they are aiming to extend their "health span" - the period of time before the diseases of ageing catch up with them.

The rough rule of thumb in nematode worms is: restrict calorie intake by 30% and see up to a 30% increase in lifespan. The effects are smaller in mice and even smaller in primates. Not many people have the willpower to adhere to a lifelong diet, though occasional "fasting mimicking diets" seem to have beneficial effects. Nevertheless the holy grail has been to find a drug that could mimic fasting. Calorie restriction flips a metabolic switch from "abundance" to "austerity". Like when you get a big salary cut, you don't go adding extensions to the house; you hunker down, live modestly, recycle your old things and delay your plans to have babies. Somehow responding to this stress also lengthens lifespan. These days researchers think autophagy plays a big part in the lengthening. For instance, recent studies on mice and humans shows that fasting accelerates the refurbishing of tissues, clearing away damaged "senescent cells" while turning on renewing stem cells.

You might think with all the epiphanies of the past 30 years, surely we know enough about ageing to go full speed ahead with interventions? All the candidate compounds, so far, seem to hack into the same pathway triggered by calorie restriction. Well, yes - but this rabbit hole goes very deep. Over the years, one compelling theory has been that it controls the integrity of mitochondria, the engines of our cells which clearly degenerate as we age. According to the theory, the corrosive by-products of cellular combustion - free radicals - cause ongoing damage as an inevitable consequence of being alive. But numerous recent experiments show that slowing the generation of free radicals in mice or flies doesn't actually slow the ageing process. In fact, it seems to have the opposite effect. Nowadays the paradigm shift is that stress signals like those from free radicals, fasting, or exercise trigger an adaptive anti-ageing response. It doesn't mean past theories are entirely wrong. It's just that there is a lot of other stuff going on in ageing as well.

None of this means the era of anti-ageing medicine has to wait for us to explore every blind alley of the rabbit hole. Indeed, most of the researchers I spoke with passionately believe they are more than ready to start testing the plethora of promising new compounds in their pipelines. What's needed is the faucet at the end - the regulatory framework that will incorporate "ageing" as a medical indication.

The human hippocampus (HC) is affected not only by pathological aging such as in Alzheimer's disease but also by the normal aging process resulting in deficits in memory, learning, and spatial navigation at old age. Magnetic resonance-studies indicate an atrophy rate of the hippocampus and the nearby parahippocampal gyrus of 2-3% per decade, which is further accelerated in the very old age where there is an annual loss of 1% over the age of 70. On the other hand more recent research has shown that the HC counts among the few brain regions with the ability to generate new neurons throughout the lifespan.

In animal models physical activity has been identified as a key mechanism that can drive this adult neuroplasticity. In humans, research has focused on the effects of aerobic fitness and training on volumes and perfusion of the HC. Results reveal that higher cardiorespiratory fitness levels (VO2 max) are associated with larger hippocampal volumes in late adulthood, and that larger hippocampal volumes may, in turn, contribute to better memory function. Furthermore, some investigations also assessed possible physiological mediators of the observed neuroplasticity, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). However, the role of cardio-respiratory fitness in modulating hippocampal gray matter volume is still under debate.

The hippocampus is also involved in spatial navigation and in motor sequence consolidation suggesting that motor skill learning and motor fitness can have impact on hippocampal volume without any cardio-respiratory change. Hence, the HC seems not only crucial for long-term memory consolidation, learning and spatial navigation, but also for balancing. Intact balance is essential for social mobility and quality of life in aging. Hence, physical intervention programs should take this function into account, too.

In this respect dancing seems to be a promising intervention since it requires the integration of sensory information from multiple channels (auditory, vestibular, visual, somatosensory) and the fine-grained motor control of the whole body. Behavioral studies have already provided evidence of better performance in balance and memory tasks in elderly dancers, but the underlying neural mechanisms have not been addressed comprehensively so far. Knowing that aerobic, sensorimotor and cognitive training contribute to hippocampal volume, which also seems to be associated with balancing capabilities, we initialized a prospective, randomized longitudinal trial over a period of 18 months in healthy seniors. Two interventions were compared: a specially designed dance program, during which subjects constantly had to learn new choreographies, and a traditional fitness program with mainly repetitive exercises.

Before and after intervention, balance was evaluated using the Sensory Organization Test and HC volumes were derived from magnetic resonance images. Fourteen members of the dance (67.21 ± 3.78 years, seven females), and 12 members of the fitness group (68.67 ± 2.57 years, five females) completed the whole study. Both groups revealed hippocampal volume increases mainly in the left HC (CA1, CA2, subiculum). The dancers showed additional increases in the left dentate gyrus and the right subiculum. Moreover, only the dancers achieved a significant increase in the balance composite score. Hence, dancing constitutes a promising candidate in counteracting the age-related decline in physical and mental abilities.

T cells and dendritic cells are common in atherosclerotic plaques. Atherosclerosis is a chronic inflammatory process in which activation of these immune cells may play a major role in the development of cardiovascular disease. Researchers developed an experimental system to directly study how these immune cells from human atherosclerotic plaques are activated in order to discover mechanisms and potential therapies. Specifically, they examined proprotein convertase subtilisin kexin 9 (PCSK9), which is known to target the low-density lipoprotein (LDL) cholesterol receptor for degradation, resulting in increased LDL levels. Knowledge of this mechanism has led to the development of PCSK9 inhibitors, which lower LDL cholesterol.

Researchers investigated the immune effects of PCSK9 on the induction of dendritic cell maturation and T cell activation by oxidised LDL. T cells were isolated from patients with atherosclerotic plaques and from healthy individuals. Human peripheral blood monocytes were differentiated into dendritic cells. The dendritic cells were pretreated with oxidised LDL and then co-cultured with T cells from atherosclerotic plaques and from blood. The researchers found that oxidised LDL promoted the maturation of dendritic cells. These dendritic cells then mediated the activation of T cells into T helper cells. Oxidised LDL also induced PCSK9. PCSK9 inhibition reversed the effects of oxidised LDL on dendritic cells and T cells. Dendritic cell maturation was repressed, as was the activation of T cells.

"We demonstrated for the first time that PCSK9 inhibition reversed the effects of oxidised LDL on immune activation. This changed a pro-inflammatory profile into an anti-inflammatory state that is potentially anti-atherosclerotic. Our study suggests that the benefits of PCSK9 inhibition extend beyond lowering LDL cholesterol."

Intrinsic skin aging is a complex biological phenomenon mainly caused by intracellular stressors. Among various factors that accelerate intrinsic aging, the major causes are cellular senescence and mitochondrial dysfunction. When proliferating cells are exposed to various types of stressors, they may undergo growth arrest, termed as cellular senescence. Senescent cells exhibit various phenomena, such as cell-cycle arrest, gene expression changes, and secretion of inflammatory cytokines. Reactive oxygen species (ROS) mainly accelerate cellular senescence and also play a role in determining the lifespan of mammalian cells. Although senescent cells are relatively rare in young organisms, their number increases with aging. Senescent cells secrete numerous factors that have harmful effects on cells.

Kaempferia parviflora Wall. ex Baker, commonly called black ginger, has been used as a dietary supplement and traditional medicine in tropical countries. K. parviflora is reported to have antioxidative, anti-inflammatory, antiviral, and anticancer activities. However, its effect on intrinsic skin aging has not been verified. We investigated the inhibitory effect of K. parviflora on intrinsic skin aging process by evaluating its effect on cellular senescence and mitochondrial dysfunction using H2O2-exposed human dermal fibroblasts. In addition, its effect on skin aging phenotypes was evaluated using hairless mice.

Based on our results, KPE was found to attenuate cellular senescence in H2O2-treated fibroblasts and hairless mice by suppressing SA-β-gal activity and the expression of cell-cycle inhibitors. The restrained expression of cell-cycle inhibitors upon KPE treatment activates the E2F group, which is responsible for cell proliferation. In addition, KPE prevents cellular senescence by regulating the PI3K/AKT signaling pathway. In conclusion, KPE delays intrinsic skin aging process by inhibiting cellular senescence and mitochondrial dysfunction. KPE does not only attenuate cellular senescence through inhibition of the p53/p21, p16/pRb, and PI3K/AKT signaling pathways but also improve mitochondrial biogenesis through PGC-1α stimulation. Consequently, KPE prevents wrinkle formation, skin atrophy, and loss of elasticity by increasing collagen and elastic fibers in hairless mice.

The Society for the Rescue of our Elders has no bylaws, incorporating documents, or other legal structure. Its sole purpose is to unite people in ways that will accelerate the availability of rejuvenation technologies to benefit all of humanity, including members of the group. The Society for the Rescue of our Elders consists of about 1,000 individuals who have demonstrated their desire to donate, invest, and/or actively participate in advancing human age reversal studies.

The Society for the Rescue of our Elders is similar to groups formed in the past to advance a science when the medical profession showed little interest. In 1767 a few wealthy and civic-minded citizens in Amsterdam gathered to form the Society for Recovery of Drowned Persons. Amsterdam is a city of canals and hence people fell in and drowned. It thus became the birthplace for the teaching and promotion of the resuscitation of dead persons. The Society for Recovery of Drowned Persons introduced scientific principles and techniques. Following successes of the Amsterdam society, rescue societies sprang up in most European capitals in the 18th century, all with the goal of finding a way of successfully resuscitating victims of sudden death. Many of these techniques (or variations of them) are used in modern emergency medical practice."

Our mission is to demonstrate statistically-significant human age reversal so that an eruption of charitable and capitalistic forces will compete to induce even longer, healthier lifespans. We live in an era whereby limitations on maximum lifespans are likely to be soon vanquished. Each day our research is delayed, we grow older and frail. There is tremendous urgency to move human rejuvenation projects forward. Funding has been secured for some clinical studies. The costs of certain projects, however, will require them to be self-funded. In these cases, each study subject will have to pay their portion of expenses of being part of the study.

The dasatinib/quercetin study of senolytics therapy will commence shortly and funding was provided by a long-time Life Extension Foundation supporter. It is divided into three phases to test different dose timing. Phase One is now fully enrolled, but other phases are still enrolling subjects. Participants can travel to Los Angeles or Idaho and must be available for two weekends in a row.

The NAD+ infusion study has commenced and funding has been secured to cover 100% of this study's cost. This study is fully enrolled. Future studies that will test NAD+ infusions for Parkinson's, Alzheimer's, and stroke patients, are being planned. Let us know if you'd like to participate. The rapamycin study site has been moved to Southern California. Funding has been secured to cover 100% of this study's cost. The primary cost of this and some other studies are the extensive clinical and biomarker measures that must be done to assess if biological age reversal is occurring. Enrollment for this study is currently open.

The GDF11 trial is planned to initiate in Nassau, Bahamas around October of this year and will require each study participant to self-fund 7,800 for one year's treatment, which includes costs of extensive clinical and biomarker measurements. A clinical trial studying the immunomodulatory properties and cost-effectiveness of mesenchymal stem cells as an alternative treatment for chronic autoimmune conditions is commencing.

The thymus regeneration study will be based in California but is available nationwide. The cost to participate in a one-year trial will be a maximum of 28,000, which includes medications, MRI scans of the thymus (optional), and high-tech monitoring of immune status. The expected re-growth of the thymus gland (based on preliminary results from a 10-patient pilot study) may provide immune restoration benefits.

Young plasma transfer studies (also called Therapeutic Plasma Exchange) will initially be conducted at several sites in Florida, North Carolina, Colorado and Southern California. We anticipate more sites in the U.S. later this year. Two treatment protocols will be offered, one using 5% albumin and immunoglobulins (plasma components derived from young donors), and the other using directed/designated young donor plasma. Comprehensive testing, including early detection testing for Alzheimer's and immune senescence markers will be offered in both protocols. The expected cost for six infusions including comprehensive measurements of possible efficacy is estimated at 50,000.

In the brains of people with Alzheimer's disease, there are abnormal deposits of amyloid beta protein and tau protein, and swarms of activated immune cells. But scientists do not fully understand how these three major factors combine to drive the disease. Researchers exposed immune cells normally found in an activated, inflammatory state in Alzheimer's brains to tiny clusters of amyloid beta - or oligomers, which are believed to be the most harmful forms of the protein. "Our thinking was that the amyloid beta oligomers would activate an inflammatory response in these immune cells, and we wanted to see if this would induce pathological forms of tau when given to neurons."

The researchers then focused on the fluid in which the immune cells had been growing. This fluid, which was filled with inflammatory factors resembled the fluid in which these cells typically live inside human brains. The team added this fluid to cultures of human cortical neurons. The neurons soon developed abnormal, bead-like swellings along their axons and dendrites. This "neuritic beading" has been seen in Alzheimer's patients and has been considered an early sign of neuronal damage, although it hasn't been clear how beading was connected to abnormal tau or if the beading led to Alzheimer's disease. The team then looked for tau in the beads and found a striking accumulation of it, though it was in an abnormal form, modified in a different way than previously thought. This modification is thought by the researchers to cause tau to become aggregated.

The finding of abnormal tau in the neuritic beads indicated that these beads could mark tau's entry into the Alzheimer's disease process. Within the beads, researchers also found high calcium levels, which are known to harm neurons and are considered an important feature of neurons in people with Alzheimer's. "We think these neuroinflammatory factors trigger this cascade. They flood the neuron with calcium. And we think that once the calcium accumulates, it causes tau to become abnormally modified. This probably leads to a snowball effect: tau detaches from microtubules and is trafficked throughout the neuron, ending up in these beads. One possibility is that these tau-filled beads are the sites where the classic tangle-like aggregates of tau will eventually emerge, which is the hallmark of Alzheimer's disease."

Researchers used mass spectrometry to sort out the amyloid beta-induced neuroinflammatory molecules that had triggered the calcium influx and neuritic beading. They were able to show that one protein in particular, MMP-9, was responsible for some of these adverse effects. "MMP-9 is an inflammatory protein shown to be elevated in the brains of Alzheimer's patients. In our study, we show that MMP-9 alone can trigger a calcium influx that floods the neuron." The researchers also identified the protein HDAC6, which originates from within neurons and concentrates in the neuritic beads. Normally, HDAC6 is thought to detect unwanted protein aggregates within neurons and transport them away for disposal. However, blocking HDAC6 stopped nearly all beads from forming in these experiments. Both of these proteins have been found to be elevated in affected areas of Alzheimer's brains. Drug companies are now developing and testing HDAC6 inhibitors, which have performed surprisingly well in early studies, although it has not been fully understood how these inhibitors work. "Our work might explain why HDAC6 inhibitors have shown such early promise."

Scientists have found that protein synthesis is overactive in people with progeria. The work adds to a growing body of evidence that reducing protein synthesis can extend lifespan - and thus may offer a useful therapeutic target to counter both premature and normal aging. "The production of proteins is an extremely energy-intensive process for cells. When a cell devotes valuable resources to producing protein, other important functions may be neglected. Our work suggests that one driver of both abnormal and normal aging could be accelerated protein turnover."

Initially, researcher were interested in whether mutation was making the lamin A protein less stable and shorter lived. After measuring protein turnover in cultured cells from skin biopsies of both progeria sufferers and healthy people, she found that it wasn't just lamin A that was affected in the disease. "We analyzed all the proteins of the nucleus and instead of seeing rapid turnover in just mutant lamin A and maybe a few proteins associated with it, we saw a really broad shift in overall protein stability in the progeria cells. This indicated a change in protein metabolism that we hadn't expected."

Along with the rapid turnover of proteins, the team found that the nucleolus, which makes protein-assembling structures called ribosomes, was enlarged in the prematurely aging cells compared to healthy cells. Even more intriguing, the team found that nucleolus size increased with age in the healthy cells, suggesting that the size of the nucleolus could not only be a useful biomarker of aging, but potentially a target of therapies to counter both premature and normal aging. The work supports other research that appears in the same issue showing that decreasing protein synthesis extends lifespan in roundworms and mice. The researchers plan to continue studying how nucleolus size may serve as a reliable biomarker for aging.

One of the last steps before treating patients with an experimental cell therapy for the brain is confirmation that the therapy works in monkeys. Researchers have now shown that monkeys with Parkinson's disease symptoms show significant improvement over two years after being transplanted neurons prepared from human induced pluripotent stem cells (iPS cells). The study is expected to be a final step before the first iPS cell-based therapy for a neurodegenerative disease.

Parkinson's disease degenerates a specific type of cells in the brain known as dopaminergic (DA) neurons. It has been reported that when symptoms are first detected, a patient will have already lost more than half of his or her DA neurons. Several studies have shown the transplantation of DA neurons made from fetal cells can mitigate the disease. The use of fetal tissues is controversial, however. On the other hand, iPS cells can be made from blood or skin, which is why researchers plan to use DA neurons made from iPS cells to treat patients.

To test the safety and effectiveness of DA neurons made from human iPS cells, researchers transplanted the cells into the brains of monkeys. It is generally assumed that the outcome of a cell therapy will depend on the number of transplanted cells that survived, but the researchers found this was not the case. More important than the number of cells was the quality of the cells. "Each animal received cells prepared from a different iPS cell donor. We found the quality of donor cells had a large effect on the DA neuron survival." To understand why, he looked for genes that showed different expression levels, finding 11 genes that could mark the quality of the progenitors. One of those genes was Dlk1. "We are investigating Dlk1 to evaluate the quality of the cells for clinical applications."

Another feature of the study that is expected to extend to clinical study is the method used to evaluate cell survival in the host brains. The study demonstrated that magnetic resonance imaging (MRI) and position electron tomography (PET) are options for evaluating the patient post surgery. The group is hopeful that it can begin recruiting patients for this iPS cell-based therapy before the end of next year.

Hundreds of genes, when manipulated, have been shown to affect the lifespan of model organisms (yeast, worm, fruit fly, and mouse). These genes, further denoted as longevity-associated genes, LAGs, could be defined as those whose modulation of function or expression results in noticeable changes in longevity - lifespan extension or accelerated aging. We have previously investigated the characteristic features of LAGs and found that (i) they display a marked diversity in their basic function and primary cellular location of the encoded proteins; and (ii) LAG-encoded proteins display a high connectivity and interconnectivity. As a result, they form a scale-free protein-protein interaction network ('longevity network'), indicating that LAGs could act in a cooperative manner.

Many LAGs, particularly those that are hubs in the 'longevity network', are involved in age-related diseases, including atherosclerosis, type 2 diabetes, cancer, and Alzheimer's disease, and in aging-associated conditions such as oxidative stress, chronic inflammation, and cellular senescence. The majority of LAGs established in yeast, worms, flies, and mice have human orthologs, indicating their conservation 'from yeast to humans'. This assumption was also supported by studies on specific LAGs or pathways such as Foxo, insulin/IGF1/mTOR signaling, Gadd45, and cell-cell and cell-extracellular matrix interaction proteins.

Now, the existing databases on orthologs allow for an essential extension of the analysis of LAG orthology, far beyond the traditional model organisms and humans. In particular, the data deposited in the InParanoid database Eukaryotic Ortholog Groups include orthologs for the complete proteomes of 273 species. Here, we report the results of an unprecedentedly wide-scale analysis of 1805 LAGs established in model organisms, available at Human Ageing Genomic Resources (HAGR) GenAge database, with regard to their putative relevance to public and private mechanisms of aging.

Our wide-scale analysis of longevity-associated genes (LAGs) shows that their orthologs are consistently overrepresented across diverse taxa, compared with the orthologs of other genes, and this conservation was relatively independent of evolutionary distance. Moreover, many worm LAGs were discovered by postdevelopmental RNA interefence on genes essential for growth and development, and this predominantly resulted in lifespan extension. That is, postdevelopmental suppression of genes that are vital early in life but are detrimental later in life, can be beneficial for longevity. The orthologs of these LAGs are also highly overrepresented across diverse taxa. Altogether, the C. elegans analysis suggests that antagonistic pleiotropy might be a highly conserved principle of aging.

An important observation in our study was that the majority of manipulations on LAG orthologs in more than one model animal resulted in concordant effects on longevity. This strengthens the paradigm of 'public' longevity pathways and of using model animals to study longevity, even across a large evolutionary distance. This notion is further strengthened when combined with the observation that the existence of an ortholog is probably accompanied by a preserved role in longevity. Yet, we also observed LAGs with ortholog presence only in a limited number of taxa, or that displayed discordant effects when tested in more than one species, which could, at least in part, be attributed to 'private' mechanisms of aging. Definitely, more comparative studies are warranted to better discriminate between private and public mechanisms, with unified methods of intervention and evaluation in mind.

Osteoporosis is caused by an imbalance between the tightly regulated process of bone formation by osteoblasts and resorption by osteoclasts. Primary osteoporosis is defined as bone loss attributed to aging or a decline in sex hormones associated with aging. This age-related osteoporosis involves the gradual loss of bone caused by insufficient bone formation.

The lack of an overall mechanistic understanding of what drives age-related osteoporosis has hindered the development of anabolic therapy appropriately targeting the etiology of the disease. It is hypothesized that decrease in the number and function of bone and bone marrow (BM)-derived mesenchymal stromal cells (MSCs) - a heterogeneous population comprising skeletal stem cells (SSCs), osteoblastic cells, and fibroblasts - lies at the root of age-related bone loss. Specifically, age-related changes in the proliferative and differentiation capacity of BM-MSCs are suspected, and recent evidence suggests that the loss of SSCs, which are a rare subset of MSCs, could be the most relevant event in the progression of senile bone loss. Thus, treatment strategies aimed at replenishing the MSCs compartment - and by extension SSCs - or augmenting endogenous populations of these cells, could result in bone growth and combat age-related osteoporosis.

A number of preclinical studies have been undertaken to determine whether MSC-based cell transplantation can induce bone formation. We have recently reported that transplantation of unmodified, low-passage MSCs prevents age-related osteoporosis in a mouse model. At the 6-month time point, we showed that transplanted animals displayed markedly increased bone formation, as well as higher osteoclast numbers. This led to improved bone quality and turnover, and importantly, sustained microarchitectural competence. Complementary to our work, studies documenting proof of principal that MSC transplantation can prevent senile osteoporosis in mouse models of accelerated aging present consistent findings.

Before the full benefit of SSC therapy can be leveraged toward bone regeneration, certain basic, translational, and clinical scientific questions will need to be answered. First, SSCs have only recently been characterized in murine models, and aside from one study documenting a BM stromal cell possessing some properties of SSCs (the generation of the hematopoietic microenvironment), this cell remains unidentified. As such, the human SSC still needs to be located, and fully characterized for phenotypic characteristics and cell surface antigen profile. Second, once identified, methods need to be developed to ensure the cell can be harvested and expanded to clinically relevant quantities. Stem cells often lose their multipotent, and self-renewal capabilities soon after removal from their native environment, therefore techniques will need to be optimized to enable large scale culture. Finally, although the safety and tumorigenic profile of MSCs has been fully evaluated and deemed safe, necessary due diligence will need to be performed on SSCs.

With over 500 clinical trials using MSCs registered with clinicaltrials.gov and numerous others being conceived, there presents a tremendous opportunity to maximize the scientific value of these expensive, laborious studies. The ability to co-operate, and leverage the availability of large, well-characterized cohorts of patients receiving MSCs (or other cell therapy/regenerative medicine agents) will maximize resource utilization. The ubiquitous nature of age-related bone loss in humans makes it an ideal candidate for regenerative medicine. Thus, we propose an ancillary study for osteoporosis to assess bone formation gains after systemic MSC transplant. By teaming up with other, even multiple, clinical trials the necessary number of patients could be more readily reached. This innovative model could be used to assess stem cell effects on various diseases in patients with existing comorbidities and chronic disease from trials that would normally only focus on one of the patient disease states. Significant savings can be achieved using an ancillary model in cell therapy due to cost sharing of expensive cell isolation, manipulation, and patient delivery.