Researchers transplanted gut microbes from old mice (24 months old) into young, germ-free mice (6 weeks old). After eight weeks, the young mice had increased intestinal growth and production of neurons in the brain, known as neurogenesis. The team showed that the increased neurogenesis was due to an enrichment of gut microbes that produce a specific short chain fatty acid, called butyrate. Butyrate is produced through microbial fermentation of dietary fibres in the lower intestinal tract and stimulates production of a pro-longevity hormone called FGF21, which plays an important role in regulating the body's energy and metabolism. As we age, butyrate production is reduced. The researchers then showed that giving butyrate on its own to the young germ-free mice had the same adult neurogenesis effects.

The team also explored the effects of gut microbe transplants from old to young germ-free mice on the functions of the digestive system. With age, the viability of small intestinal cells is reduced, and this is associated with reduced mucus production that make intestinal cells more vulnerable to damage and cell death. However, the addition of butyrate helps to better regulate the intestinal barrier function and reduce the risk of inflammation. The team found that mice receiving microbes from the old donor gained increases in length and width of the intestinal villi - the wall of the small intestine.

"It is intriguing that the microbiome of an aged animal can promote youthful phenotypes in a young recipient. This suggests that the microbiota with aging have been modified to compensate for the accumulating deficits of the host and leads to the question of whether the microbiome from a young animal would have greater or less effects on a young host. The findings move forward our understanding of the relationship between the microbiome and its host during ageing and set the stage for the development of microbiome-related interventions to promote healthy longevity."

The gut microbiota evolves as the host ages, yet the effects of these microbial changes on host physiology and energy homeostasis are poorly understood. To investigate these potential effects, we transplanted the gut microbiota of old or young mice into young germ-free recipient mice. Both groups showed similar weight gain and skeletal muscle mass, but germ-free mice receiving a gut microbiota transplant from old donor mice unexpectedly showed increased neurogenesis in the hippocampus of the brain and increased intestinal growth.

Metagenomic analysis revealed age-sensitive enrichment in butyrate-producing microbes in young germ-free mice transplanted with the gut microbiota of old donor mice. The higher concentration of gut microbiota-derived butyrate in these young transplanted mice was associated with an increase in the pleiotropic and prolongevity hormone fibroblast growth factor 21 (FGF21). An increase in FGF21 correlated with increased AMPK and SIRT-1 activation and reduced mTOR signaling. Young germ-free mice treated with exogenous sodium butyrate recapitulated the prolongevity phenotype observed in young germ-free mice receiving a gut microbiota transplant from old donor mice. These results suggest that gut microbiota transplants from aged hosts conferred beneficial effects in responsive young recipients.

For the past 10 years, Yale Professors David Spiegel and Jason Crawford have been working on tools to enable the development of glucosepane-cleaving drugs. Kizoo Technology Capital investors say now is the time to advance this groundbreaking research toward the clinic and are leading funding of a new company, Revel Pharmaceuticals Inc., founded by Drs. David Spiegel, Jason Crawford, and Aaron Cravens. Kizoo leads the seed financing round at Revel, with Oculus co-founder Michael Antonov participating. SENS Research Foundation provided funding to the Yale GlycoSENS group for several years.

The long-lived collagen proteins that give structure to our arteries, skin, and other tissues are continuously exposed to blood sugar and other highly reactive molecules necessary for life. Occasionally, these sugar molecules will bind to collagen and form toxic crosslinks that alter the physical properties of tissues and cause inflammation. As a result, tissues slowly stiffen with aging, leading to rising systolic blood pressure, skin aging, kidney damage, and increased risk of stroke and other damage to the brain. Perhaps the most important of these Advanced Glycation End-product (AGE) crosslinks is a molecule called glucosepane. Revel is developing therapeutics that can cleave glucosepane crosslinks thus maintaining and restoring the elasticity of blood vessels, skin, and other tissues, and preventing the terrible effects of their age-related stiffening.

The Yale group's first major milestone - the first complete synthesis of glucosepane - was highly recognized when published. Since then progress has been rapid, with development of glucosepane binding antibodies and discovery of therapeutic enzyme candidates capable of breaking up glucosepane crosslinks. Revel will build upon this progress by advancing the first GlycoSENS therapeutics into the clinic.

"This is truly a first. Revel will open an entirely new category in repairing a significant damage of aging - crosslinking of collagen. Glucosepane crosslinks may cause not only wrinkles on your face but also lead to age-related rising blood pressure and possibly stroke. Collagen is the infrastructure of our bodies - in every tissue, supporting cellular function and health - but with aging, this critical molecular infrastructure accumulates damage. By clearing out this damage, we can restore tissue function and repair the body. Revel is one of only a few companies taking a repair-centric approach to treat diseases of aging and one day our AGE-cleaving therapeutics will undo this damage at the molecular level."

Hematopoiesis is a complex process through which hematopoietic stem cells (HSCs) generate all the cell types found in the blood. This originates during the early stages of embryonic development and continues in the bone marrow (BM) throughout adulthood to preserve homeostasis in the blood system. The interest in the expansion and production of HSCs has increased in recent years. After the derivation of human embryonic stem cells (ESCs) and the discovery of cellular reprogramming, much effort has been devoted to obtain HSCs and mature blood cells from human pluripotent stem cells (PSCs).

In addition to their unlimited, yet-to-be realized, therapeutic potential, human PSCs make a very useful tool that can be utilized to understand the signaling pathways involved in hematopoiesis. Recently, long term engraftment and multi-lineage differentiation of hPSCs-derived hematopoietic progenitor cells was achieved after screening large numbers of potential transcription factors that were activated in vivo following transplantation in mice. Ideally, the generation of functional HSCs with the same capacity in vitro would allow deep interrogation of the differentiation process, and, eventually, the generation of therapeutic grade cells.

Human PSCs represent a promising versatile source of cells for regenerative medicine. The fact that they could be derived from patients' somatic cells and undergo clonal expansion in culture makes them ideal for the regeneration of the blood system. Their potential with regard to treating genetic blood disorders could be augmented when combined with genome editing techniques.

However, two main hurdles limit the translation of induced pluripotent stem cell (iPSC) derived HSCs into cellular therapies. First, the generation of functional iPSC-derived HSCs capable of long-term engraftment and full reconstitution of the blood system. Second, the long-term safety of the generated cells. HSCs derived from iPSCs remain transcriptionally and epigenetically distinct from cord blood HSCs. The impact of these differences on the safety and functionality of the generated HSCs is yet to be investigated.

Many researchers are now taking a second look at tau protein, once dismissed as simply a "tombstone" marking dying cells, and investigating whether tau may in fact be an important biological driver of Alzheimer's disease. In contrast to amyloid, which accumulates widely across the brain, sometimes even in people with no symptoms, autopsies of Alzheimer's patients have revealed that tau is concentrated precisely where brain atrophy is most severe, and in locations that help explain differences in patients' symptoms (in language-related areas vs. memory-related regions, for example).

"No one doubts that amyloid plays a role in Alzheimer's disease, but more and more tau findings are beginning to shift how people think about what is actually driving the disease. Still, just looking at postmortem brain tissue, it has been hard to prove that tau tangles cause brain degeneration and not the other way around. One of our group's key goals has been to develop non-invasive brain imaging tools that would let us see whether the location of tau buildup early in the disease predicts later brain degeneration."

Researchers recruited 32 participants with early clinical stage Alzheimer's disease, all of whom received PET scans using two different tracers to measure levels of amyloid protein and tau protein in their brains. The participants also received MRI scans to measure their brain's structural integrity, both at the start of the study, and again in follow-up visits one to two years later.

The researchers found that overall tau levels in participants' brains at the start of the study predicted how much degeneration would occur by the time of their follow up visit (on average 15 months later). Moreover, local patterns of tau buildup predicted subsequent atrophy in the same locations with more than 40 percent accuracy. In contrast, baseline amyloid-PET scans correctly predicted only 3 percent of future brain degeneration. "Seeing that tau buildup predicts where degeneration will occur supports our hypothesis that tau is a key driver of neurodegeneration in Alzheimer's disease."

β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer's disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients' diagnostic and prognostic evaluation.

In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict the subsequent brain atrophy, measured using longitudinal magnetic resonance imaging that is acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid-PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients.

This data supports disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient's progression and design future clinical trials.

Mitochondria are both the primary source of organismal energy and the major source of cellular reactive oxygen species (ROS) and oxidative stress during aging. Aged cardiac mitochondria are functionally changed in redox balance and are deficient in ATP production. Numerous reported studies have focused on redox stress and ROS production in aging. However, in its simplistic form, the free radical theory of aging has become severely challenged.

While more attention has been placed on mitochondrial electron leak and consequent free radical generation, proton leak is a highly significant aspect of mitochondrial energetics, as it accounts for more than 20% of oxygen consumption in the liver and 35% to 50% of that in muscle in the resting state. There are two types of proton leak in the mitochondria: 1) constitutive, basal proton leak, and 2) inducible, regulated proton leak , including that mediated by uncoupling proteins (UCPs). In skeletal muscle, a majority of basal proton conductance has been attributed to adenine nucleotide translocase (ANT). Although, aging-related increased mitochondrial proton leak was detected in the mouse heart, kidney, and liver by indirect measurement of oxygen consumption in isolated mitochondria, direct evidence of functional impact remains to be further investigated. Moreover, the exact site and underlying mechanisms responsible for aging-related mitochondrial proton leak are unclear.

SS-31 (elamipretide) binds to cardiolipin-containing membranes and improves cristae curvature. Prevention of cytochrome c peroxidase activity and release has been proposed as its major basis of activity. SS-31 is highly effective in increasing resistance to a broad range of diseases, including heart ischemia reperfusion injury, heart failure, neurodegenerative disease, and metabolic syndrome. In aged mice, SS-31 ameliorates kidney glomerulopathy and brain oxidative stress and has shown beneficial effects on skeletal muscle performance. We have recently shown that administration of SS-31 to 24 month old mice for 8 weeks reverses the age-related decline in diastolic function, increasing the E/A ratio from just above 1.0 to 1.22, restoring this parameter 35% towards that of young (5 month old) mice. However how SS-31 benefits and protects aged cardiac cells remains unclear.

In this report we investigated the effect and underlying mechanism of action of SS-31 on aged cardiomyocytes, especially on the mitochondrial proton leak. Using the naturally aged rodent model we provided direct evidence of increased proton leak as the primary energetic change in aged mitochondria. We further show that the inner membrane protein ANT1 mediates the augmented proton entry in the old mitochondria. Most significantly, we demonstrate that SS-31 prevents the proton entry and rejuvenates mitochondrial function through direct association with ANT1 and stabilization of the ATP synthasome.

Up to date, treatments for hair loss (alopecia) include pharmacological and surgical (autologous hair transplant) interventions. Although hair restoration surgery is nowadays the most effective method, donor hair follicles (HFs) scarcity is often its major limitation. Besides, pharmacological treatments still not fully satisfy the patient's needs and entail drastic side effects. Thus, the limited efficacy and possible side effects of the current treatments have fostered the search for alternative therapeutic solutions, capable of generating unlimited number of HFs de novo.

Of note, stem cell-based tissue engineering is emerging as the most thriving approach, aiming to reconstruct HFs in vitro to replace lost or damaged HFs as a consequence of disease, injury, or aging. HF bioengineering approaches are based on the accumulated knowledge on reciprocal epithelial-mesenchymal (EM) interactions controlling embryonic organogenesis and postnatal HF cyclic growth. However, despite recent progress in the field, clinical applications of tissue engineering strategies for hair loss are still missing. Neogenesis of human follicles derived from cultured HF dermal cells has not been successfully achieved yet.

A regenerative medicine therapy for human hair loss will only be successfully achieved when HF are formed de novo following implementation of in vitro bioengineered structures into the patient's bald scalp. Importantly, although from a scientific perspective studies have achieved and reported HF regeneration from human cells, the caveats are whether (a) there is any mouse contribution in HF neogenesis from human bioengineered structures transplanted into mouse skin, and (b) human bioengineered structures will generate HF that besides growing/cycling also mimetic natural hair type and are responsive to physiological stimuli.

Moreover, significant limitations may further hamper an operational clinical solution for hair loss. First, bioengineered hair reconstruction will imply large-scale production of cell-based structures and the development of well-defined culture expansion media for clinical usage. Robust culture systems that allow stem cell expansion while maintaining their intrinsic properties are still missing. Second, even if generation of functional and cycling HF units is achieved, a huge gap still exists until the conception of a clinically relevant bioengineered product that responds to physiological stimuli (eg, neuronal stimuli) and aesthetic context (hair type, density, pigmentation, and orientation).

Atrial fibrillation (AF) is associated with increased mortality due mainly to heart failure and embolic complications. AF is well known to occur more frequently with increasing age and is linked to vascular aging. During AF, inflammation, apoptosis, endothelial dysfunction, and platelet activation contribute to creating a prothrombotic state and promoting atrial remodeling. While the link between aging and thrombogenicity is well established, the cellular and molecular mechanisms are still under consideration.

Premature cellular senescence is an irreversible form of cell cycle arrest that can be triggered by various cellular stresses, including DNA damage, oxidative stress, and oncogene activation. It is characterized by the acquisition of a proinflammatory and prothrombotic profile. Senescent cells are found in aged tissues where they remain metabolically active but are unable to proliferate despite the presence of mitogens.

In AF, the role of senescence in atrial remodeling and the development of a prothrombotic state remains unclear. Using a model of atrial endothelial cells, we recently demonstrated that thrombin, a key determinant of thrombogenicity during atrial fibrillation, promotes atrial endothelial cells senescence and the acquisition of the senescence-associated secretory phenotype, characterized by enhanced expression levels of vascular cell adhesion molecule (VCAM)-1, tissue factor (TF), transforming growth factor (TGF-β), and metalloproteinases (MMP-2 and MMP-9).

In this study, we investigated the link between AF and senescence markers through the assessment of protein expression in the tissue lysates of human appendages from patients in AF, including paroxysmal (PAF) or permanent AF (PmAF), and in sinus rhythm (SR). The major findings of the study indicated that the progression of AF is strongly related to the human atrial senescence burden as determined by p53 and p16 expression. The stepwise increase of senescence (p53, p16), prothrombotic (TF), and proremodeling (MMP-9) markers observed in the right atrial appendages of patients in SR, PAF, and PmAF points toward multiple interactions in the human atrium that enhance the senescence burden, atrial extracellular matrix remodeling, thrombogenicity, and other putative mediators involved in the progression of AF.

The beneficial functions of mesenchymal stem cells (MSCs) decline with age, limiting their therapeutic efficacy for myocardial infarction. Macrophage migration inhibitory factor (MIF) promotes cell proliferation and survival. We investigated whether MIF overexpression could rejuvenate aged MSCs and increase their therapeutic efficacy in myocardial infarction. Young and aged MSCs were isolated from the bone marrow of young and aged donors. Young MSCs, aged MSCs, and MIF-overexpressing aged MSCs were transplanted into the peri-infarct region in a rat myocardial infarction model.

Aged MSCs exhibited a lower proliferative capacity, lower MIF level, greater cell size, greater senescence-associated-β-galactosidase activity, and weaker paracrine effects than young MSCs. Knocking down MIF in young MSCs induced cellular senescence, whereas overexpressing MIF in aged MSCs reduced cellular senescence. MIF rejuvenated aged MSCs by activating autophagy, an effect largely reversed by the autophagy inhibitor 3-methyladenine.

MIF-overexpressing aged MSCs induced angiogenesis and prevented cardiomyocyte apoptosis to a greater extent than aged MSCs, and had improved heart function and cell survival more effectively than aged MSCs four weeks after myocardial infarction. Thus, MIF rejuvenated aged MSCs by activating autophagy and enhanced their therapeutic efficacy in myocardial infarction, suggesting a novel MSC-based therapeutic strategy for cardiovascular diseases in the aged population.

Fibrosis is a shared pathological characteristic of many fatal lung diseases, such as idiopathic pulmonary fibrosis (IPF), which exhibits epithelial cell senescence and abundant foci of highly activated pulmonary fibroblasts. To date, there is no effective cure for these fibrotic diseases, as there is an incomplete understanding of the pathogenesis. In the progression of IPF, epithelial cell senescence has been demonstrated to occur in IPF and experimental lung fibrosis models. However, the underlying mechanism between epithelial cell senescence and pulmonary fibroblast activation remain to be elucidated.

In our study, we demonstrated that Nanog, as a pluripotency gene, played an essential role in the activation of pulmonary fibroblasts. In the progression of IPF, senescent epithelial cells could contribute to the activation of pulmonary fibroblasts via the senescence-associated secretory phenotype (SASP). Cell-cell contact between epithelial cells and fibroblasts appears to be essential in signalling cascades and important for wound repair. Pulmonary fibroblasts co-cultured with senescent epithelial cells expressed higher levels of collagen I, vimentin, and α-SMA, suggesting that senescent epithelial cells could effectively induce the activation of pulmonary fibroblasts.

We found that activated pulmonary fibroblasts will exhibit aberrant activation of Wnt/β-catenin signalling and elevated expression of Nanog. Further study revealed that the activation of Wnt/β-catenin signalling was responsible for senescent epithelial cell-induced Nanog phenotype in pulmonary fibroblasts. Thus the targeted inhibition of epithelial cell senescence or Nanog could effectively suppress the activation of pulmonary fibroblasts and impair the development of pulmonary fibrosis, indicating a potential for the exploration of novel anti-fibrotic strategies.

Inflammation is initiated as the body's immune cells activate inflammatory cascades to prevent tissue damage from injury or infiltrating antigens. Within the central nervous system, microglia, known as 'the brain's immune cells,' interact with astrocytes and neurons by assuming phagocytic phenotypes and releasing inflammatory cytokines. This can cause neurodegeneration, phagocytosis of synapses, diminished neural function, microglial activation, inflammatory cytokine release, and further microglial activation until threat to the neural environment abates. Activation of astrocytes, termed astrogliosis, also occurs as part of the inflammatory process.

When acute, this neuroinflammatory response is necessary and even beneficial to the neural environment in eliminating pathogens or aiding brain repair. However, when extreme threats to the neural environment such as protein aggregates (i.e., lewy bodies, neurofibrillary tangles) accumulate in the brain and protractedly sustain inflammation, continuous gliosis and apoptosis can occur as a result of unregulated inflammatory cytokine release. Continuity of this activated state results in chronic inflammation, which is implicated in virtually all neurological disorders, including Alzheimer's disease, Parkinson's disease, and ALS.

Overexpression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine with a central role in microglial activation, has been associated with neuronal excitotoxicity, synapse loss, and propagation of the inflammatory state. Thalidomide and its derivatives, termed immunomodulatory imide drugs (IMiDs), are a class of drugs that inhibit TNF-α production. Due to their multi-potent effects, several IMiDs, including thalidomide, lenalidomide, and pomalidomide, have been repurposed as drug treatments for diseases such as multiple myeloma and psoriatic arthritis. Preclinical studies of currently marketed IMiDs, as well as novel IMiDs, support the development of IMiDs as therapeutics for neurological disease. IMiDs have a competitive edge compared to similar anti-inflammatory drugs due to their blood-brain barrier permeability and high bioavailability, with the potential to alleviate symptoms of neurodegenerative disease and slow disease progression.

TGF-β exerts diverse functions by modulating the expression of downstream target genes via transcriptional and post-transcriptional mechanisms as well as protein modulation in a context-dependent manner. Importantly, the downstream targets of TGF-β signaling include many regulators involved in multiple aspects of aging processes, such as cell proliferation, cell cycle regulation, the production of reactive oxygen species (ROS), DNA damage repair, telomere regulation, unfolded protein response (UPR), and autophagy. Due to a large overlap between the two pathways, TGF-β signaling exhibits multifaceted crosstalk with aging processes. At the cellular level, TGF-β signaling has been shown to play an important role in cellular senescence and stem cell aging. Furthermore, the alteration of TGF-β signaling pathways has been frequently observed in various age-related diseases, including cardiovascular disease, Alzheimer's disease (AD), osteoarthritis, and obesity.

TGF-β has been shown to have dual functions in cancer biology: An early tumor suppressor and a late tumor promoter. The cytostatic effects of TGF-β are mediated by inducing the cyclin-dependent kinase inhibitors p15Ink4b, p21, and p27, and by suppressing several proliferation factors including c-Myc. This suggests a senescence promoting role of TGF-β under normal conditions and also coincides with the tumor suppressing role of cell senescence. TGF-β has been shown to induce or accelerate senescence and senescence-associated features in various cell types. In addition, the TGF-β-mediated accumulation of senescent cells has been suggested in idiopathic pulmonary fibrosis (IPF).

In addition to the cytostatic mechanisms, the senescence-promoting role of TGF-β might be explained by the effects on other modulators of senescent phenotypes. TGF-β reportedly induces ROS production in the mitochondria in several cell types. In addition, TGF-β suppresses telomerase activities by downregulating the expression of telomerase reverse transcriptase (TERT) in various cell types. Further, the senescence-associated secretory phenotype (SASP) yields the production and secretion of various signaling molecules, importantly including TGF-β. Thus, TGF-β is secreted as one of the SASP factors and can induce and maintain senescent phenotype and age-related pathological conditions in an autocrine/paracrine manner.

Researchers have identified synergistic cellular pathways for longevity that amplify lifespan fivefold in C. elegans, a nematode worm used as a model in aging research. The research draws on the discovery of two major pathways governing aging in C. elegans, which is a popular model in aging research because it shares many of its genes with humans and because its short lifespan of only three to four weeks allows scientists to quickly assess the effects of genetic and environmental interventions to extend healthy lifespan.

Because these pathways are "conserved," meaning that they have been passed down to humans through evolution, they have been the subject of intensive research. A number of drugs that extend healthy lifespan by altering these pathways are now under development. The discovery of the synergistic effect opens the door to even more effective anti-aging therapies.

The new research uses a double mutant in which the insulin signaling (IIS) and TOR pathways have been genetically altered. Because alteration of the IIS pathways yields a 100 percent increase in lifespan and alteration of the TOR pathway yields a 30 percent increase, the double mutant would be expected to live 130 percent longer. But instead, its lifespan was amplified by 500 percent.

A new study provides new evidence of an association between cardiorespiratory fitness and brain health, particularly in gray matter and total brain volume - regions of the brain involved with cognitive decline and aging. Brain tissue is made up of gray matter, or cell bodies, and filaments, called white matter, that extend from the cells. The volume of gray matter appears to correlate with various skills and cognitive abilities.

The researchers found that increases in peak oxygen uptake were strongly associated with increased gray matter volume. The study involved 2,013 adults from two independent cohorts. Participants were examined in phases from 1997 through 2012. Cardiorespiratory fitness was measured using peak oxygen uptake and other standards while participants used an exercise bike. MRI brain data also was analyzed.

The results suggest cardiorespiratory exercise may contribute to improved brain health and decelerate a decline in gray matter. The most striking feature of the study is the measured effect of exercise on brain structures involved in cognition, rather than motor function. "This provides indirect evidence that aerobic exercise can have a positive impact on cognitive function in addition to physical conditioning. Another important feature of the study is that these results may apply to older adults, as well. There is good evidence for the value of exercise in midlife, but it is encouraging that there can be positive effects on the brain in later life as well."

Researchers wanted to investigate if increasing the number of stem cells in the brain would help in recovering cognitive functions, such as learning and memory, that are lost during ageing. The research group stimulated the small pool of neural stem cells that reside in the brain in order to increase their number and, as a result, to also increase the number of neurons generated by those stem cells. To achieve this goal, researchers used a gene therapy to produce overexpression of the cell cycle regulators Cdk4/cyclinD1. Surprisingly, additional neurons could survive and form new contacts with neighbouring cells in the brain of old mice.

Next, the scientists examined a key cognitive ability that is lost, similarly in mice and in humans, during ageing: navigation. It is well known that individuals learn to navigate in a new environment in a different way depending on whether they are young or old. When young, the brain can build and remember a cognitive map of the environment but this ability fades away in older brains. As an alternative solution to the problem, older brains without a cognitive map of the environment need to learn the fixed series of turns and twists that are needed to reach a certain destination. While the two strategies may superficially appear similar, only a cognitive map can allow individuals to navigate efficiently when starting from a new location or when in need of reaching a new destination.

Would boosting the number of neurons be sufficient to counteract the decreasing performance of the brain in navigation and slow down this ageing process? The answer is "yes": old mice with more stem cells and neurons recovered their lost ability to build a map of the environment and remembered it for longer times making them more similar to young mice. Even better, when neural stem cells were stimulated in the brain of young mice, cognitive impairments were delayed and memory was better preserved over the entire course of the animal natural life. In young individuals, a brain area called the hippocampus is crucial for remembering places and events, and is also responsible for creating maps of new environments. However, old individuals use other structures that are more related to the development of habits. It was very interesting to see that adding more neurons in the hippocampus of old mice allowed them to use strategies typical of young animals.

Epistasis analyses using mutant strains in lower organisms such as Caenorhabditis elegans (C. elegans) have revealed genes required for the effects of calorie restriction (CR), referred to here as CR genes, and the signal pathways mediating the effects of CR. In C. elegans, a number of genes such as aak-2, daf-16, skn-1, clk-1, and pha-4 have been reported to be associated with the life-prolonging effect of CR. Some of these genes also mediate the effects of CR in mice. Previous studies also reported that mutations of single genes (referred to here as longevity genes) can extend lifespan even in ad libitum feeding animals.

Many of these genes can be functionally categorized into genes associated with nutrient sensing or metabolic responses. Among these gene mutations, reduction- or loss-of-function mutations of genes in the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) signaling consistently extend lifespan in a range of organisms. Since CR is known to decrease the plasma concentration of GH and IGF-1, the GH-IGF-1 pathway is considered an evolutionary conserved pathway for longevity and a main aspect of the mechanism of CR.

Thus far, a total of 112 CR genes in yeast, 62 in nematode, 27 in drosophila, and seven in mice have been identified . Among these genes, forkhead box protein O 3 (Foxo3) and sirtuin 1 (Sirt1) genes are common in mice, nematodes, and flies. CR and longevity gene models have elucidated signal pathways for the extension of lifespan, although the signal pathways are context dependent.