It was reported over 50 years ago that old age is associated with depletion and loss of function of stem cells. Since that time, there has been extensive research confirming the deleterious effects of aging on all types of stem cells, and a growing belief that such age-related changes in stem cells further accelerate tissue and organismal aging. There have also been hundreds of early-phase clinical trials using mesenchymal stem cells (MSCs) for a wide range of disorders including graft-versus-host disease, autoimmune disease, and heart disease where both regenerative and immunomodulatory effects of MSC are harnessed.

The possibility that stem cells might be "vehicles for youthful regeneration of aged tissues" has been well recognized. Mesenchymal stem cells from young mice infused into old mice improved age-related osteoporosis and also increased life span. Transplantation of stem cells from young mice to old mice has also been reported to improve cardiac and reproductive function. There is clearly an opportunity to now undertake clinical trials to explore the therapeutic potential for stem cell transplants for age-related conditions in older humans.

Frailty provides an ideal target for clinical trials of MSC transplantation and aging. Frailty in older humans is associated with reduced circulating MSC, while many of the clinical features of frailty involve mesenchymal tissues, that is, the musculoskeletal system. In clinical practice, the diagnosis is often made based on clinical impression rather than any formal diagnostic process. The definitions of frailty overlap with definitions of aging and sarcopenia. Frailty can be considered to be the end-stage consequence of the biological processes of aging and accumulated chronic disease. Recently two clinical trials were published on the effects of MSC transplantation in frail older humans, and these trials represent potential landmarks in the treatment of frailty. Both studies are early-phase trials of a small number of participants, designed primarily to assess safety, so conclusions about efficacy need to be treated with caution. Even so, the results are striking and, at minimum, pave the way for large randomized Phase III clinical trials.

The first study was a Phase I open-label trial where allogeneic MSC collected from the bone marrow of younger donors aged 20-45 years were used to treat 15 frail patients (average age 78 years) using a single infusion of either 50, 100, or 200 million cells. After 6 months, outcomes that improved included the 6-minute walk and tumor necrosis factor α (TNFα) levels, with variable improvements in forced expiratory volume in 1 second (FEV1), Mini-Mental State Examination (MMSE), and quality of life. No significant adverse effects were recorded, and only one patient developed antibodies that could potentially neutralize the outcomes.

The second study by the same group was a Phase II randomized, double-blinded trial of allogeneic MSC at two doses (100 or 200 million cells) versus placebo. The participants were 30 frail patients with an average age of 76 years. No therapy-related adverse effects were documented at 1 month. Improvements were reported for physical performance, the 6-minute walk test, short physical performance exam, FEV1, and TNFα mostly in the 100 million cell groups. The authors conclude that the treated groups had "remarkable improvements" in outcomes. There are always caveats associated with interpreting efficacy in small numbers of subjects, yet it is remarkable that a single treatment seems to have generated improvement in key features of frailty that are sustained for many months.

The purpose of this Phase 1 pilot study, AllogeneiC Human Mesenchymal Stem Cell in Patients with Aging FRailTy via IntravenoUS Delivery (CRATUS), was to evaluate the safety and tolerability of allogeneic hMSCs (allo-hMSCs) in patients with aging frailty and to explore domains of treatment efficacy of allo-hMSCs through the reduction of signs and symptoms of aging frailty. The major new findings of CRATUS are that intravenous allo-hMSC infusions are safe and well tolerated in elderly individuals with early signs and symptoms of frailty. Importantly, there were improvements in a constellation of parameters that are important predictors of morbidity and mortality in patients with aging frailty.

With no current standard of care for frailty, allo-hMSCs may hold great promise as a cell therapy agent for patients with this syndrome. The underlying basis for positive effects of allo-MSCs are likely due, at least in part, to anti-inflammatory and proregenerative effects. In this regard, frailty is characterized by systemic inflammation and low "reserve capacity" of organ systems thought due to diminished endogenous stem cell production. Replenishment of the body's stem cell "factory" and/or revitalization of stem cell niches via intravenous infusion of allo-hMSCs may help treat the morbidities associated with aging frailty.

There are no specific medical or biologic treatments that ameliorate or reverse frailty. Stem cell depletion is a key mechanism postulated to contribute to frailty. In this regard, we recently conducted a phase I open label study of human allogeneic mesenchymal stem cells (allo-hMSCs) intravenously infused for frailty, which showed that the cells could be safely administered, improved measures of functional capacity, and reduced inflammation. Therefore, we conducted the current phase II double-blinded and placebo-controlled study in order to test the hypothesis that exogenous allo-hMSCs could reverse signs and symptoms of frailty in older individuals.

Similar approaches have been shown to exert beneficial effects on the cardiovascular system, with functional improvements on various types of heart disease, endothelial function, and systemic inflammation. Given their pleiotropic mechanisms of action, which include antifibrotic, anti-inflammatory, proangiogenic properties, and their ability to stimulate endogenous progenitor cells, we hypothesize that their use may offer a novel treatment strategy in frail patients.

The findings here replicate in large part the results of the earlier open label study, support the concept that MSCs have bioactivity against aging frailty, and confirm the fact that 100 million cells represents a superior dose level compared to 200 million. The reasons underlying the inverse dose relationship noted here remain incompletely understood. The 100 million dose group produced significant improvements in both physiologic and immunologic markers of frailty, while the high dose group solely demonstrated positive immunomodulatory effects.

Immune senescence results from defects in T-cell immunity and is also characterized by a low-grade chronic inflammatory state. Little is known about the source of the inflammation that fuels most age-related diseases; however, it may derive from an age-related decline in homoeostatic immune function, resistance to endogenous microbes or senescent cells. The senescent phenotype is not just proliferative arrest; rather, it is a widespread change in protein expression and secretion, including pro-inflammatory cytokines, chemokines, growth factors and proteases, termed the senescence-associated secretory phenotype or SASP. Consequently, senescent cells can alter the tissue microenvironment and affect neighbouring cells through paracrine signalling.

The SASP was originally thought to result from persistent activation of the DNA damage response; however, it is now known to be regulated by p38 MAPK, which was shown to be both necessary and sufficient for its development in fibroblasts. The chronic and sustained activation of p38 MAPK differs substantially from the response to acute stress and was found to follow the kinetics of SASP development. Furthermore, siRNA interference of p38 MAPK was shown to significantly reduce the secreted levels of most SASP factors. To date, the SASP has predominantly been characterized in fibroblast cell culture models or aged mice, with very few reports of a SASP being found in the human immune system with either age or differentiation.

Senescent CD8+ T cells are found within the CD27-CD28- population, and these highly differentiated T cells can be further divided using CD45RA. T cells that re-express CD45RA within this subset have multiple characteristics of senescence, including a low proliferative activity, high levels of DNA damage and the loss of telomerase activity. We have also shown that p38 MAPK signalling, which is increased in highly differentiated CD8+ T cells, is involved in the loss of telomerase activity and proliferative capacity and that blockade of p38 MAPK activity with a specific small-molecule inhibitor can restore both proliferation and telomerase activity in these cells. However, surprisingly the CD45RA-re-expressing senescent T cells do not have critically short telomeres, suggesting that senescence in these cells may be induced by other mechanisms including DNA damage by increased reactive oxygen species production.

In this study, we demonstrate that irrespective of the derivation of CD8+ CD45RA+CD27- T cells, these primed cells exhibit a unique highly inflammatory secretory profile characteristic of the SASP, and we also provide evidence that ADAM28 can be used as a functional marker of senescence in CD8+ T cells. Furthermore, we show that the secretory phenotype in CD8+ CD45RA+CD27- T cells is controlled through p38 MAPK signalling, which contributes to age-associated inflammation.

Studies of dietary restriction, a reduction in nutrient intake without malnutrition, in a diverse array of organisms have revealed it to be an effective way to extend lifespan and promote broad-spectrum improvement in health during aging. Early work focused on total caloric intake as the driving force behind these beneficial effects, but studies that have comprehensively examined the effects of individual macronutrients on lifespan underscore the importance of protein-to-carbohydrate ratio. In the fruit fly, Drosophila melanogaster, yeast restriction has been used as an alternative to wholesale dilution of the diet to effectively extend female fly lifespan. These effects have also been observed in mammals, where protein restriction increased rodent lifespan. Together, these studies establish that the life-extending benefits associated with dietary restriction can be achieved without reducing total caloric intake when the relative consumption of protein to carbohydrates is low.

A striking feature of the effects of dietary restriction is its acute nature, yielding beneficial outcomes with short-term application. In Drosophila, a switch to a restricted diet reduced short-term mortality risk within 48 hr, and in mice, 1 week of protein starvation decreased tissue damage caused by temporary blockage of blood flow during surgical operation, greatly improving survival following renal ischemic injury. Even ad libitum feeding of low-protein, high-carbohydrate diets for 8 weeks resulted in metabolic improvement in mice compared to those fed high-protein, low-carbohydrate diets.

A significant threat to global health is infectious diseases. Acute preventative strategies that strengthen immunity prior to such procedures are therefore of strong interest. To answer the questions of whether, similar to general health and aging, innate immune function is acutely modulated by individual nutrients, we executed a comprehensive analysis of the effects of dietary composition on survival following pathogenic infection in Drosophila. Although lacking adaptive immunity, insects are equipped with innate immunity, which is an ancient first-line defense mechanism that recognizes the pattern of invading microorganisms as well as their virulence factors. Drosophila innate immunity has humoral and cellular components, and this innate immune response is highly conserved between Drosophila and mammals.

Here, we present evidence that yeast restriction, but not carbohydrate restriction, substantially improves fly survival following bacterial infection through several components of innate immunity. We find that yeast-restriction-mediated enhancement of innate immunity is orchestrated by components of the target of rapamycin (TOR) signaling network, in which reduced TOR signaling results in a stabilization of the transcription factor Myc through its suppressor protein phosphatase 2A. Myc in turn mediates a sustained induction of genes that encode antimicrobial peptides, which are effective bacterial killers. These results implicate a function for protein phosphatase 2A (PP2A) and Myc as signaling molecules that serve to potentiate the immune response in yeast-restricted animals following pathogenic infection.

Accumulation of abnormally folded amyloid beta peptide (Aβ) in cerebral amyloid plaques is the pathologic hallmark of Alzheimer's disease (AD). Aβ originates from the amyloid precursor protein (APP), a membrane protein expressed in many tissues and synapses of neurons with unknown function. A group of specific enzymes named secretases cleave APP into distinct fragments. APP cleavage by β-secretase and then γ-secretase leads to pathological Aβ oligomers. Oligomers are the units which form protofibrils and later fibrils and plaques. Genetic models of AD are typically established by excessively expressing Aβ protein and the current hypothesis of AD etiology centers around amyloid plaques.

Unlike the complexity and controversy in AD, the pathogenesis of osteoporosis is known as an imbalance between bone formation and mineralization. Hyperparathyroidism, Vitamin D deficiency, and steroid use are common causes of osteoporosis. Osteoporosis is mostly asymptomatic until minor trauma or falls lead to fractures. Bone formation involves bone matrix production and mineralization, whereas bone resorption is a biological erosive process mediated by osteoclasts. When the balance leans toward bone resorption, bone mineral density (BMD) decreases and osteoporosis develops.

Bone resorption is driven by the receptor activator nuclear factor-kappa B ligand (RANKL) / receptor activator nuclear factor-kappa B (RANK) signaling network, a signaling complex with multiple downstream pathways. The binding of RANKL to RANK triggers the cascade. Amyloid deposition in the brain and RANKL signaling are two seemingly independent pathways leading to AD and osteoporosis. The possible linkage between these two pathways has been investigated by measuring osteoclast activities in a transgenic mice model of AD. Both in vitro and in vivo examinations showed enhanced Aβ expression in bone, together with increased adipose tissue formation in the marrow space, analogous to osteoporotic bones. The abnormally expressed amyloid deposition appears to interfere with the RANKL signaling cascade and in turn the balance between bone formation and bone resorption. Similar findings extend to human studies.

Previous observational studies have reported the increased frequency of comorbid osteoporosis in AD. The relationship between these two diseases is more likely one of shared etiology than one condition causing the other. The overexpression of Aβ may take place in both brain and bone, interfering with the RANKL signaling cascade, enhancing osteoclast activities, and leading to osteoporosis. There is a growing body of evidence from in vitro and in vivo studies that the AD pathology in the brain can be reflected by examining the bone. Future investigation will focus on assessing biomarkers of cognitive aging in patients with osteoporosis and looking into the bone microstructure of patients with AD.

Reproduction is an energetically expensive process that supposedly impairs somatic integrity in the long term, because resources are limited and have to be allocated between reproduction and somatic maintenance, as predicted by the life history trade-off model. The consequence of reduced investment in somatic maintenance is a gradual deterioration of function, i.e. senescence. However, this classical trade-off model gets challenged by an increasing number of contradicting studies that show no negative effect of high metabolic rate on lifespan, or even a positive association. Consequently, more research is needed to gather representative data from animals with different life histories, to gain a comprehensive understanding of how life history trade-offs influence lifespan.

Ansell's mole-rats (Fukomys anselli) are subterranean rodents with an extraordinary long lifespan, 22 years being the maximum recorded age thus far. They live in multigenerational families where typically only the founder pair (breeders) reproduces. Most of the offspring (non-breeders) forego reproduction and remain in the natal family. A clear contradiction to the classic trade-off model has been shown in this species: breeding individuals live up to twice as long as their non-breeding counterparts, a feature which is unique amongst mammals. Previous studies showed that daily activity between breeders and non-breeders does not show differences, and social rank does not influence life expectancy. Hence, extrinsic factors like aggression, fighting and higher workload in non-breeders are not likely to influence the lifespan difference. Here, we test the hypothesis that breeders and non-breeders of Ansell's mole-rats differ in their mass specific resting metabolic rate (msRMR), as a possible approach to understand the bimodal aging pattern.

Low msRMR is a common trait in bathyergid rodents interpreted as an adaptation to the subterranean habitat, and our measurements generally confirm previous studies. However, our finding that long-lived breeders of F. anselli have higher metabolic rates compared to shorter-lived non-breeders is novel. This aspect is most interesting since investment in reproduction was long thought to impair somatic maintenance according to the classical trade-off model, but recent findings refer to the trade-off model as being too simplistic. Especially in terms of female reproduction, a meta-analysis from different homeothermic vertebrates has shown that in intraspecific comparisons between breeders and non-breeders, breeders had lower levels of oxidative damage in certain tissues.

This effect could be attributed to upregulation of antioxidant defense mechanisms, such as glutathione or superoxide dismutase activity, which shows a tissue-dependent upregulation in several species during reproduction. This oxidative shielding hypothesis, even if not consistent across different studies, suggests a reproduction-induced protection of mothers and offspring. Ansell's mole-rats are continuously reproducing once they achieve the reproductive status. Oxidative shielding might protect the animals from detrimental pregnancy effects due to a higher energy turnover in female breeders compared to non-breeders. However, the bimodal lifespan in Ansell's mole-rats is not sex-dependent, indicating a general effect in terms of reproductive status, msRMR, and lifespan rather than just a pregnancy effect restricted to females.

Oxidative stress as a main factor contributing to life history trade-offs is getting challenged by increasing contradictory studies. The uncoupling-to-survive hypothesis complements simplistic theories of senescence by explaining apparent exceptions. It suggests that elevated oxygen consumption, a measure for msRMR in the present study, could be also observed due to uncoupling of proton flux in the mitochondria. This process, also referred to as inducible proton-leak, is facilitated by uncoupling proteins and increases RMR. On the other hand, inducible proton-leak is known to reduce ROS production by reducing mitochondrial membrane potentials. Hence the higher msRMR measured in breeders of Ansell's mole-rats could be due to higher rates of mitochondrial uncoupling compared to non-breeders.

Several studies found higher rates of uncoupling in those laboratory mice that lived longer compared to other individuals with shorter lifespans. However, in the case of mole-rats this model should be considered carefully, since in naked mole-rats, surprisingly high levels of oxidative damage to DNA, lipids and proteins were found, which contrasts with the proposed benefit of mitochondrial uncoupling. In general, our finding stresses the complexity of currently discussed aging mechanisms.

Hypertension affects about 40% of those aged over 25 and is a major risk factor for heart disease, stroke and kidney failure. An interdisciplinary group of scientists found that conventional medication aimed at reducing high blood pressure restored normal vascular rhythms only in the largest blood vessels but not the smallest ones. "It is clear that current anti-hypertensive treatments, while successfully controlling blood pressure, do not restore microvascular function."

Based on a networks physiology approach, the researchers compared a group aged in their twenties and two older groups aged around 70 - one with no history of hypertension and the other taking medications for high blood pressure. In the older group being treated for high blood pressure the drug treatment restored normal function at the level of arterioles and larger vessels. But when the researchers studied the nonlinear dynamical properties of the smallest blood vessels in the body, they found differences between the two older groups.

"Specifically, current hypertensive treatment did not fully restore the coherence or the strength of coupling between oscillations in the heart rate, respiration, and vascular rhythms (vasomotion). These are thought to be important in the efficient and adaptive behaviour of the cardiovascular system. Indeed, one aspect of ageing is the progressive physiological weakening of these links that keep the cardiovascular system reactive and functional. The results have not only confirmed previous observations of progressive impairment with age of the underlying mechanisms of coordination between cardiac and microvascular activity, but for the first time have revealed that these effects are exacerbated in hypertension. Current antihypertensive treatment is evidently unable to correct this dysfunction."

Whether changes in internal body environment affect kidney aging remains unclear. Specifically, it is unknown whether transplanted kidneys from older donors recover from tissue damage after placement in younger recipients. In this study, a parabiosis animal model was established to investigate the effects of a young internal body environment on aged kidneys.

The animals were divided into six groups: young (Ycon) and old (Ocon) control groups, isochronic youth-youth group (Y-IP), elderly-elderly group (O-IP) and heterochronic youth (Y-HP) elderly (O-HP) group. After parabiosis, tubule and interstitial tissue scores in the O-HP group were significantly lower than in the Ocon and O-IP groups. The expression of aging-related protein p16 and senescence-associated β-galactosidase in the O-HP group was significantly reduced compared with the Ocon and O-IP groups. Autophagy factor Atg5 and LC3BII were significantly upregulated, while the expression of the autophagic degradation marker (P62) was significantly downregulated in the O-HP group compared with the Ocon and O-IP groups.

With the same comparison, the positive cells of TUNEL staining and the expression of inflammatory cytokines IL-6 and IL-1β were significantly reduced, while the total/cleaved caspase-3 and total/pNF-κB were significantly increased in the O-HP group. The results demonstrated that a young blood environment significantly reduces kidney aging. These findings provide new evidence supporting an increase in the upper age limit for human kidney transplantation donors.

The maintenance of cellular and organismal homeostasis determines the progress of aging. On a cellular level, homeostasis is maintained, in part, through macroautophagy (hereafter referred to as autophagy), a conserved mechanism by which a cell achieves multiple goals, including clearance of misfolded proteins and organelle turnover with subsequent recycling of degraded constituents. As cells age, their ability to perform these functions declines. This likely leads to an unsustainable accumulation of protein aggregates, which ultimately present an obstacle to cellular survival. Indeed, studies of the distinct signaling networks in C. elegans that modulate lifespan have provided evidence of a central role for autophagy in many known longevity paradigms.

Thus loss of protein and organelle quality control secondary to reduced autophagy is a hallmark of aging. However, the physiologic and molecular regulation of autophagy in long-lived organisms remains incompletely understood. Here we show that the Kruppel-like family of transcription factors are important regulators of autophagy and healthspan in C. elegans, and also modulate mammalian vascular age-associated phenotypes.

Kruppel-like family of transcription factor deficiency attenuates autophagy and lifespan extension across mechanistically distinct longevity nematode models. Conversely, Kruppel-like family of transcription factor overexpression extends nematode lifespan in an autophagy-dependent manner. Furthermore, we show the mammalian vascular factor Kruppel-like family of transcription factor 4 (KLF4) functions to regulate autophagy in vascular endothelial cells and modulate blood vessel aging in mice. KLF4 expression also decreases with age in human vascular endothelium. Thus, Kruppel-like family of transcription factors constitute a transcriptional regulatory point for the modulation of autophagy and longevity in C. elegans with conserved effects in the murine vasculature and potential implications for mammalian vascular aging.

Biomedical engineers report a significant advance in efforts to repair a damaged heart after a heart attack, using grafted heart-muscle cells to create a repair patch. The key was overexpressing a gene that activates the cell-cycle of the grafted muscle cells, so they grow and divide more than control grafted cells. Up to now, an extremely low amount of engraftment of cardiomyocytes has been a stumbling block in hopes to use grafted cells to repair hearts after a heart attack. Without the successful repair that a graft could potentially offer, the damaged heart is prone to later heart failure and patient death.

In experiments in a mouse model, researchers showed that gene overexpression of the cell-cycle activator CCND2 increased the proliferation of grafted cardiomyocytes. This led to increased remuscularization of the heart at the dead-tissue site of the heart attack, a larger graft size, improved cardiac function and decreased size of the dead tissue, or infarct. Besides regenerating muscle, the grafted cells also increased new blood vessel formation at the border zone of the infarct, apparently through increased activation of the paracrine mechanism. The team used cardiomyocytes that were derived from human induced pluripotent stem cells, as they work toward a goal of eventual clinical treatment for human heart attack patients.

Researchers first showed that overexpression of CCND2 in the human induced pluripotent stem cells-derived cardiomyocytes, or hiPSC-CMs, increased the proportion of cells that exhibited markers for the S and M phases of the cell-cycle, and for cytokinesis, as measured in cell culture. When they injected overexpressing hiPSC-CMs into the infarct region and the border of the infarct in the mouse model, the left ventricle ejection fraction was significantly greater at week four and the infarct size was significantly smaller, as compared with mice receiving normal hiPSC-CMs that did not overexpress CCND2. Both treatments were improvements as compared with untreated mice. Overexpression also led to an increased number of engrafted hiPSC-CMs, as measured by bioluminescence and human cell markers.

I'm sure you've noticed that the Life Extension Advocacy Foundation has been shouting from the rooftops for quite a while that rejuvenation biotechnologies need to happen, and we're doing our best to make them happen as soon as possible. The job isn't easy; the fact that numerous people still raise concerns about the idea doesn't make it any easier, and we invest part of our time duly addressing those concerns. But the discussion about what might go wrong or how to prevent this or that hypothetical problem might draw attention away from another, possibly even more important question: why do we strive to make rejuvenation a reality? There's not much point in doing something if it yields no benefits, especially if that something requires as much hard work as this cause does; so, what are the expected benefits of rejuvenation?

Health: rejuvenation, we have said time and again, is pretty much all about health. The causal link between biological aging and pathologies is well established, and even when we account for the few elderly who are exceptionally healthy for their age, we're left with the obvious fact that the older you are, the sicker you are - and even the aforementioned exceptions aren't in the best of shape. To the best of my knowledge, the number of people who actively wish to be sick at some point tends to be fairly small; so, when you think that a truly comprehensive rejuvenation platform would allow people to maintain youthful health irrespective of their age, the health benefits of rejuvenation become crystal clear.

Independence: frailty, failing senses, weakness, and diseases aren't good friends of independence, but they are good friends of old age. That's why nursing homes exist in the first place - to take care of elderly people who are no longer independent. Again, even the few exceptional cases who manage on their own until death don't have it easy. Having people doing things for you can be nice in small doses, but having to have people doing things for you, not so much. Rejuvenation would eliminate the health issues that make the elderly dependent on others.

Longevity: as odd as it may sound, longevity is really just a 'side effect' of health, because you can't be healthy and dead. The longer you're healthy enough to be alive, the longer you'll live. Since rejuvenation would keep you in a state of youthful health, the obvious consequence is that you'd live longer. How much longer exactly is hard to say, but as long as you're healthy enough to enjoy life, it's safe to say that longevity would be a benefit; you'd have more time and energy to dedicate to what you love doing, and you could keep learning and growing as a person for an indefinitely long time.

Ultimately, all of these perks can be summarised into one: choice. If we had fully working rejuvenation therapies available and were thus able to keep ourselves always perfectly healthy, regardless of our age, we could choose whether we wanted to use these therapies or not. Those who wish a longer, healthier life could avail themselves of the opportunity and escape aging for as long as they wanted; those who prefer to age and bow out the traditional way could just as easily not use the therapies. Rejuvenation would give us an extra option we currently don't have; everyone is forced to face the burden of aging and eventually die of it, for the moment. Being able to choose what we wish for ourselves is one of the most fundamental human rights and an obvious, unquestionable benefit.

Skin, intestine and blood are composed of short-lived cells that require continuous replenishment by somatic stem cells to maintain tissue homeostasis. Current theory is therefore that especially aging of stem cells that form these tissues will greatly contribute to the decline in tissue function with aging. Identifying mechanisms of stem cell aging and conditions under which aged stem cells become functionally similar to young stem cells might be important first steps towards devising treatments of aging-associated imbalance in tissue homeostasis and tissue regeneration with the ultimate goal of allowing for healthy aging.

Cdc42 belongs to the Rho GTPase family of the Ras superfamily, acting as a binary molecular switch that cycles between a GTP-bound active state and GDP-bound inactive state in response to a variety of extracellular stimuli. A key function of Cdc42 is regulation of elements that structure cells like the actin cytoskeleton or part of the microtubule network, which is believed to be a central mechanism for Cdc42-mediated cell polarization, adhesion and migration. Another important function of Cdc42 is to regulate cell growth signaling. It is becoming clear that the function and signaling pathways regulated by Cdc42 are tissue and cell type-specific, and the general principles of Cdc42 function defined by in vitro methods or from one tissue cell type may or may not apply to another cell type in in vivo situations. This also means that observations for example from fibroblasts (from which most of the information stems) might be informative for designing targeted experiments, but ultimately, in which pathway and function Cdc42 may operate in aged HSCs needs to be stringently dissected in HSCs and can not just be inferred from data obtained in other types of cells or systems.

Cell polarity is well characterized in epithelial cells and neuronal stem cells, but was only recently described to also exist in HSCs. Studies support a critical role of polarity in stem cell maintenance. What might be the role of polarity in stem cells? Polarity can be associated with specialized and compartmentalized functions in HSCs, with migration or with division. A defining feature of stem cells is their ability to maintain a balanced number of stem cells (self-renewal), while at the same time being able to generate specialized progeny (differentiation). Both processes depend on the ability of stem cells to undergo either symmetric or asymmetric divisions, which involve cell polarity.

Supporting a determining role for polarity in stem cell aging is a recent study showing that a loss of proper polarity in aged Drosophila germ-line stem cells correlates with their reduced function. To date, the role of HSC polarity with respect to the mode of HSC division and cell fate potential of daughter cells has not been experimentally tested. Given the established role of Cdc42 in mediating morphologic polarity in many cell types and in regulating HSC differentiation, it has been somewhat logical to postulate that Cdc42 plays a role in coordinating polarity in HSCs.

Genome-wide association studies of longevity in humans linked elevated expression of Cdc42 in hematopoietic cells to increased morbidity and aging. The holy grail of aging research is the question of rejuvenation. Are molecular mechanisms of aging reversible? If elevated Cdc42 activity is causally linked to stem cell aging and apolarity, then reversion of the level to the level found in young HSCs might result in "younger" HSCs. Aged HSCs, in which Cdc42 activity level was, via pharmacological inhibition, reduced to the level found in young mice, presented functionally and upon transplantation almost identically to young HCS. This suggests that Cdc42 activity might represent a novel target to rejuvenate aged HSCs via altering stem cell polarity.

The most common neurodegenerative disorder, Alzheimer's disease is characterized by the buildup of amyloid plaques and neurofibrillary tangles in several brain regions. The leading hypothesis for its pathogenesis is the amyloid cascade - which suggests that the amyloid beta-protein, and particularly the amyloid-beta 42 peptide, initiates the disease process. An imbalance between the production and clearance of amyloid-beta results in the protein's aggregation into larger plaques that lead to the death of brain cells and the cognitive symptoms seen in Alzheimer patients. Several potential treatments have been developed that specifically target amyloid, but none have been effective in halting disease progression.

Amyloid-beta is produced by the cleavage of the larger amyloid precursor protein (APP) by an enzyme called gamma-secretase. Previous research led to the development of gamma-secretase inhibitors that totally block the function of the enzyme, but in clinical trials these drugs produced serious side effects through their effects on the processing of other proteins. As an alternative, researchers first developed the concept of gamma-secretase modulators (GSMs), which change but do not totally suppress the enzyme's activity, back in 2000. More recently reseearchers developed a group of soluble GSMs, one of which - SGSM-36 - appeared to be a promising candidate for clinical development.

In the current study, the researchers showed that three days of treatment with SGSM-36 reduced levels of amyloid-beta 42 in the brains and plasma of a validated mouse model of inherited Alzheimer's without affecting the processing of APP by other enzymes. In cellular models they compared the action of SGSM-36 to that of semagacestat, one of the gamma-secretase inhibitors that failed in clinical trials. While SGSM-36 treatment only reduced levels of the toxic amyloid-beta 40 and 42 peptides, semagacestat reduced all form of amyloid as well as gamma-secretase processing of other proteins, including the important signaling protein Notch, reduction of which may have caused the toxic effects of gamma-secretase inhibitor treatment.

"Genetic, biochemical, molecular biological and pathological evidence all support the hypothesis that excessive accumulation of amyloid-beta - particularly amyloid-beta 42 - is the primary event leading to Alzheimer's related pathology. In our future studies, we will be testing SGSM-36 against similar molecules that may have equal or higher potency in reducing amyloid-beta 42 and further investigating its molecular mechanisms in animal models, with the eventual goal of testing its potential in clinical trials."