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- Will Increased Understanding of Cellular Senescence Lead to an End to Cancer?
- Papers Drawn from the Ongoing Investigation of Naked Mole-Rat Biochemistry
- Preliminary Evidence for Senescent Microglia to Contribute to Synucleinopathies
- Oxidative Stress Disrupts Excitation-Contraction Coupling in Aging Muscles
- Repair Biotechnologies Closes Seed Round, Joins Grapeseed.bio Incubator
- Decellularized Lungs Successfully Transplanted in Pigs
- Attempts Continue to Link Blood Group to Natural Variations in Longevity
- Does Neuroplasticity Undergo Less of a Decline with Age than Thought?
- If Life is Good, Why So Eager to Set a Schedule to Leave it Behind?
- Hydrogen Sulfide Influences Cellular Senescence via Splicing Mechanisms
- Removing Tau Enhances Brain Function in Young Mice
- Autophagic Flux Does Not Decline with Age in Dermal Fibroblasts
- A Review of Neurogenesis in the Aging Brain
- Juvenesence Expands its Support of AgeX Therapeutics
- Theorizing that Adult Neurogenesis is Linked to Olfactory Function
Will Increased Understanding of Cellular Senescence Lead to an End to Cancer?
Selective destruction of senescent cells in old tissues offers the promise of some degree of rejuvenation, coupled with effective therapies for a range of age-related diseases that currently cannot be controlled. In the past few years, a number of companies have raised venture funding for the development of senolytic therapies, those capable of removing some portion of senescent cells with an acceptable side-effect profile. The potential market is enormous, and thus despite the many potential competitors, any new mechanism by which senescent cells can be destroyed might be the pathway to success and revenue for the individuals and organizations involved in that research. A great deal more attention and funding is being devoted to the biochemistry of senescent cells than was the case even five years ago.
Cellular senescence is also of great interest to cancer researchers. Senescence in response to DNA damage is a way in which our biochemistry removes the riskiest cells from circulation. Senescence irreversibly shuts down the ability to replicate, senescent cells secrete signals to attract the immune system to the vicinity, so that problem cells can be destroyed, and in any case most senescent cells self-destruct shortly after entering this state. This works quite well at the outset, but not all senescent cells are destroyed. Eventually, there are enough of them that their signaling results in significant inflammation and disarray in the surrounding tissue - and that actually helps the development of cancer.
Nonetheless, at the front line of cancer research, any reliable approach that can force cancer cells into senescence is a win. Today's paper describes the possible foundation for such a treatment. While this isn't good for the patient in the long term - much of the shortened life expectancy of chemotherapy patients is most likely due to their high burden of senescent cells - it is a much better option than the outcome of uncontrolled cancer. It seems quite plausible that one of the results of the present raised level of interest in senescent cell biochemistry will be a range of more selective, more reliable, better ways to force cancer cells into senescence; approaches that rely on cellular biochemistry that is common to many or all cancers. That can then be coupled with senolytic therapies: turn the cancerous cells senescent and immediately destroy them. Might there be a practical end to cancer somewhere in the senescence research of the next decade or two? Maybe so.
Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth
Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function. Among the genes coding for the MYST family of KATs are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF). KAT6A has essential roles in normal haematopoietic stem cells and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers.
KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus, a function that requires its KAT activity. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer.
Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.
In summary, using high-throughput screening followed by medicinal chemistry optimization, in-cell assays, biochemical assessment of target engagement, and tumour models in mice and fish, we have developed a novel class of inhibitors for a hitherto unexplored category of epigenetic regulators. These inhibitors engage the MYST family of lysine acetyltransferases in primary cells, specifically induce cell cycle exit and senescence, and are effective in preventing the progression of lymphoma in mice.
Papers Drawn from the Ongoing Investigation of Naked Mole-Rat Biochemistry
A sizable amount of effort is devoted to the comparative biology of aging, and in particular mapping the noteworthy differences between naked mole-rats and other similar-sized rodent species. Naked mole-rats live nearly ten times longer than mice and are near immune to cancer. It is possible that a sufficiently comprehensive understanding of why this is the case could result in therapies for humans, though I believe the odds of this coming to pass in the near future of the next couple of decades are much larger for cancer than aging. Research into calorie restriction mimetic drugs has demonstrated that safely inducing even small shifts in the operation of metabolism, even when aiming to mimic states that occur naturally and are very well studied, is very expensive and very slow work. While naked mole-rat resistance to cancer may boil down to just a couple of mechanisms, any one of which might be exploited alone, their longevity most likely has many contributing factors, and will be much harder to map and understand.
The open access papers noted here report on what are fairly standard fishing expeditions into the cellular biochemistry of the naked mole-rat, comparing it with that of the guinea pig. This sort of work takes place throughout the research community, and in many contexts. Researchers pick likely tissues and processes to examine, and then compare as much genetic, epigenetic, and proteomic data as they have the capacity to produce and process. Differences are pulled up from the depths for examination, and theories advanced based on what is presently known. Of the findings in these papers, some reinforce earlier theories on the damage resistance of specific cellular components in naked mole-rats, particularly mitochondria, while the most interesting item is the presence of raised levels of enzymes that are protective against oxidative damage. Past research has shown that older naked mole-rats appear to have all the signs of high levels of oxidative stress, but are largely unaffected by it.
Naked mole-rat transcriptome signatures of socially suppressed sexual maturation and links of reproduction to aging
Naked mole-rats (NMRs) are eusocially organized in colonies. Although breeders carry the additional metabolic load of reproduction, they are extremely long-lived and remain fertile throughout their lifespan. This phenomenon contrasts the disposability theory of aging stating that organisms can invest their resources either in somatic maintenance, enabling a longer lifespan, or in reproduction, at the cost of longevity. Here, we present a comparative transcriptome analysis of breeders vs. non-breeders of the eusocial, long-lived NMR vs. the polygynous and shorter-lived guinea pig (GP).
Comparative transcriptome analysis of tissue samples from ten organs showed, in contrast to GPs, low levels of differentiation between sexes in adult NMR non-breeders. NMRs show functional enrichment of status-related expression differences associated with aging. Lipid metabolism and oxidative phosphorylation - molecular networks known to be linked to aging - were identified among most affected gene sets. Remarkably and in contrast to GPs, transcriptome patterns associated with longevity are reinforced in NMR breeders.
Species comparison of liver proteomes reveals links to naked mole-rat longevity and human aging
Our cross-species analysis revealed that the liver of NMRs possesses three major characteristics compared to GP: (i) lower rate of mitochondrial respiration, due to reduced protein levels of complex I; (ii) higher reliance on fatty acids for energy production, deriving from increased abundance of enzymes responsible for lipid turnover; and (iii) increased expression of detoxifying enzymes.
Naked mole-rats have a very low metabolic rate, which reaches only 40% of the value predicted for a mammal in relation to body mass. They further have a very poor ability of thermoregulation and one of the lowest body temperatures of 32°C known among mammals. These traits likely serve as energy-saving adaptations to their arid environment. An inverse relationship between body temperature and expected lifespan has been reported, which suggests a contribution of the low body temperature of NMR to their longevity. These adaptations, as well as their high resistance to hypoxia, may account for a large proportion of the unique metabolic differences of NMR compared to other mammals.
Consistent with the established and published knowledge on NMR phenotypes at old age, we have shown a clear impact of aging on the NMR liver proteome that negatively affects the abundance of proteins involved in lipid metabolism and detoxification processes. The same pathways are similarly affected with aging also in mice and humans. Our observations support the notion of an extremely low, but detectable, rate of aging in NMRs.
Two major questions arise from our work: how NMRs have evolved their particular liver metabolism, and how does this contribute to the extreme longevity of these animals? Multiple studies have previously linked the composition of the mitochondrial respiratory chain to lifespan extension in multiple species. Similarly, lipid homeostasis and signaling has been linked to health and longevity, and changes in lipid metabolism have been shown to mediate the positive effects of anti-aging dietary interventions. Our data show that in both NMR and human liver, there is a progressive decline of enzymes responsible for fatty acid turnover. These alterations might contribute to changes in energy metabolism that favor the accumulation of adipose tissue and increased inflammation at older age.
From a mechanistic point of view, it is conceivable that adaptation to the particular ecosystem of NMRs has selected for characteristics of energy metabolism that in turn enabled extreme longevity via activation of stress pathways. Among these, the NFE2L2 pathway, which controls the expression of many of the detoxifying enzymes that we found increased in NMR vs. GP, was shown to have enhanced activity in NMR. The activities of the same pathways tend to decline during aging, as shown here by the decline of their target genes in both NMR and humans and in different model organisms. It is therefore tempting to speculate that their higher basal activity in the NMR might contribute to its enhanced stress resistance and ultimately delay the aging process.
Preliminary Evidence for Senescent Microglia to Contribute to Synucleinopathies
The evidence of the past decades, and particularly the past seven years, strongly supports the idea that the accumulation of senescent cells is a root cause of aging. Cells become senescent in large numbers day in and day out, a normal end of life state for somatic cells that have reached the Hayflick limit. Cells also become senescent as the result of damage, or a toxic environment, and there is ever more of that with advancing age. Near all of these cells are destroyed quite quickly after they enter a senescent state, but enough linger to ensure that a few percent of all cells are senescent in old age. These problem cells secrete a potent mix of signals that induces chronic inflammation, degrades tissue structure, and alters the behavior of normal cells for the worse.
Senescent cells are not the only component of aging, but given enough time senescent cells alone would be able to kill you. Senescent cells are a prominent cause of fibrosis and declining function of organs such as the lungs, kidneys, liver, and heart. They cause arthritis. Ever more immune cells are senescent in later life. The list goes on, and scientists are adding to it with each passing month, as ever more is discovered of the role of senescent cells in specific age-related conditions. The research I'll point out today is an example of the type, in this case early evidence that indicates senescent microglia in the brain are a contributing cause of synucleinopathies such as Parkinson's disease.
Synucleinopathies are associated with the aggregation of solid deposits of α-synuclein in the aging brain. Neurons are harmed by the halo of surrounding biochemistry that arrives alongside the presence of these protein aggregates. This is a similar story to that related to amyloid-β and tau: deposits in the brain; an associated collection of molecules and interactions that harm neurons; the association with age-related neurodegeneration. It will be most interesting to see how the exploration of cellular senescence in the supporting cells of the brain plays out in this context over the years ahead. How much of this protein aggregation in aging is driven by the secretions of senescent cells, and how greatly can the onset of these conditions be delayed by targeted destruction of those senescent cells?
Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity
An example of the changing environment in the aging brain is the changes in the supporting cells in the brain, including microglia. Healthy microglia monitor their environment, phagocytosing debris, and releasing numerous molecules that can impact other cells. Activated microglia can act as antigen presenting cells and activate T-cells. After an infection has been dealt with microglia can recruit cells that are involved in neuronal repair and secrete anti-inflammatory cytokines. The idea of aging microglia stems from histological observations of healthy aged brains where the cells often develop dystrophic phenotypic characteristics. Dystrophic microglia have also been associated with the increased release of toxic reactive oxygen species and inflammatory cytokines and impaired phagocytic ability. However, one of the most unique changes observed in dystrophic microglia in the aging brain is the very high accumulation of iron, which is found to be stored in proteins, such as ferritin.
The presence of healthy glial cells is critically important to neuronal wellbeing. Microglia maintain homeostasis in the healthy brain and fight infection, when it is present, through a complicated system of signalling molecules. The importance of microglia to neurons is supported by higher incidence of dystrophic microglia and microglial apoptosis in Alzheimer's disease. The inflammation of the nervous system in neurodegenerative disease was thought to be due to activated microglia. However, low, but sustained, release of inflammatory factors and impaired neuroprotective ability of microglia seen in neurodegeneration could be due to dystrophic changes instead.
The cytosolic protein alpha-synuclein (α-syn) is associated with a range of neurodegenerative diseases, including Parkinson's disease (PD). In PD there has been discussion of the possible involvement of microglia and experiments with rodent PD models have shown that microglial activation can cause PD-like symptoms. In the current work, we establish iron overload as a mechanism to switch microglial phenotype to one that has many of the characteristics of senescent microglia. Iron overload was achieved by growing microglia in high concentrations of iron. We also show that iron overloaded (iron-fed) microglia release factors, including increased levels of the cytokine TNFα that caused an increased expression of α-syn, altered its activity, and increased its aggregation.
Developing a model of senescent/dystrophic microglia in vitro has numerous issues. Chief among these is the lack of clarity in defining dystrophic microglia. There is currently no single molecular marker that would define a dystrophic or senescent microglial cell. Proteomics/transcriptomics based studies comparing microglia from old and young brains have been carried out for both mouse and human but have yielded conflicting results. However, there is a general cellular senescence signature that all cells show and this is no different for microglia, which also show characteristics aligning with a senescence-associated secretory phenotype.
Synucleinopathies are associated with the aggregation of α-syn in cells and this is believed to stem from two causative processes. The first and most well recognized is an increased expression of α-syn, resulting in molecular crowding. Using conditioned medium from our model dystrophic microglia, we were able to induce increased α-syn expression and increased aggregation in SH-SY5Y cells. Thus, by the incorporation of an aspect of brain aging we were able to induce several aspects of the disease state in neuronal cells. For this reason, we believe that we have developed a simple and valuable tool for the exploration of the molecular mechanisms behind synuclein related diseases and possibly other neurodegenerative diseases.
Oxidative Stress Disrupts Excitation-Contraction Coupling in Aging Muscles
Sarcopenia is the name given to loss of muscle mass and strength that occurs with age. When it comes to assembling evidence for causes of the condition, this is one of the better examples of the present state of understanding in aging. A sizable number of potential causes have convincing evidence, all may be relevant, but the degree to which they are important relative to one another is hard to discern. Further, the layering of the causative mechanisms, how they interact, and whether and to what degree some are secondary to others, is also hard to discern. The only truly reliable method of answering such questions is to fix just one contributing cause, and observe the results. The field of biotechnology is on the verge of being able to achieve that goal for sarcopenia and a number of other age-related conditions, but not quite there yet.
What is the usual approach given the inability to fix a cause of age-related disease in isolation? Make it worse instead. The research community can break cellular biochemistry in ways that exaggerate certain manifestations of aging - such as the oxidative stress under examination in today's open access paper. It is, however, very challenging to say whether or not such a study produces results that are useful or actionable. Forms and amounts of damage that do not occur in normal aging produce results that might superficially resemble aspects of aging, might tell us something, or might be completely irrelevant to our understanding of aging. The details matter, and they are wildly different in every case, and sometimes the research community simply doesn't have a good enough understanding of the specific mechanisms to be able to mount a good argument as to whether or not the study is useful.
Among the candidates for contributing causes of sarcopenia are chronic inflammation, loss of stem cell activity, dysregulation of dietary protein processing necessary for tissue growth, decline of nerve-muscle junctions, and reduced density of capillary networks and thus a reduction in nutrient supply to tissues. There are others. The paper here looks at rising levels of oxidative stress, increased amounts of reactive oxidizing molecules generated by cells and roaming throughout tissues; these molecules cause damage that must be repaired, but more importantly trigger all sorts of cellular reactions that, collectively, don't help the situation. This is an aspect of aging that goes hand in hand with chronic inflammation, and is secondary to deeper causes that include mitochondrial dysfunction and cellular senescence.
Oxidative stress-induced dysregulation of excitation-contraction coupling contributes to muscle weakness
Sarcopenia, the age-related loss of muscle mass and strength, is a major cause of morbidity and mortality in the elderly population. While muscle atrophy contributes to weakness, the decline in muscle strength is more rapid than the atrophy, suggesting a deficit in intrinsic force-generating properties of the muscle. The age-related muscle weakness independent of loss of mass is defined as dynapenia and involves the excitation-contraction coupling machinery of the muscle fibres. A progressive increase in cellular oxidative stress during ageing has been implicated as a major contributor to sarcopenia.
Excitation-contraction coupling involves a sequence of events whereby action potential-driven excitation of the sarcolemma results in rapid changes in cytoplasmic calcium concentration leading to activation of force-generating machinery in the sarcomere. In mammalian skeletal muscle, this process may dictate the rates of relaxation and a termination of a variety of Ca2+-dependent signalling pathways and gene transcription events that influence muscle quality and quantity. These processes imply the critical importance of calcium handling in the muscle fibre as dysregulation of calcium homoeostasis has been associated with reduced specific force in ageing and conditions of increased oxidative stress.
Our lab has previously used a mouse model of oxidative stress that was created by deleting cellular antioxidant enzyme Cu/Zn superoxide dismutase (Sod1-/-) resulting in many features of rapid and accelerated sarcopenia. The reduction in specific force in these mice is only partially rescued via direct muscle stimulation that bypasses the neuromuscular junction, suggesting a loss of functional innervation in these mice but also defects within fibres. Moreover, interrogation of the function of single permeabilized fibres showed no difference between Sod1-/- and wild-type (WT) mice indicating no impairment in the Sod1-/- mice in the inherent function of the contractile machinery and suggests that there may be declines in the functioning of the excitation contraction machinery.
The goal of this study was to determine whether the loss of innervation and the chronic increase in cellular oxidative stress in the Sod1-/- mice affect the excitation-contraction apparatus in a manner similar to muscles of old WT mice. We report that the disruption of excitation-contraction coupling contributes to impaired force generation in the mouse model of Sod1 deficiency. Briefly, we found a significant reduction in sarcoplasmic reticulum Ca2+ ATPase (SERCA) activity as well as reduced expression of proteins involved in calcium release and force generation. Another potential factor involved in EC uncoupling in Sod1-/- mice is oxidative damage to proteins involved in the contractile response.
In summary, this study provides strong support for the coupling between increased oxidative stress and disruption of cellular excitation contraction machinery in mouse skeletal muscle. The novel quantitative mechanistic data provided here can lead to potential therapeutic interventions of SERCA dysfunction for sarcopenia and muscle diseases.
Repair Biotechnologies Closes Seed Round, Joins Grapeseed.bio Incubator
I had promised a short update on progress at Repair Biotechnologies, the company that Bill Cherman and I founded earlier this year to help advance the state of therapies to treat aging, and here it is. We recently closed a seed round with a number of investors in our close-knit community, and are presently setting up our modest headquarters near Syracuse, NY, alongside our allies at Ichor Therapeutics. The staff at Ichor, fresh from a sizable investment made by Juvenescence in their subsidiary Antoxerene, have launched an incubator, Grapeseed.bio, to encourage the development of new companies focused on the treatment of aging. Repair Biotechnologies is the first such company to be accepted to the program.
Our initial development program at Repair Biotechnologies progresses, and I'm pleased to be able to say that we have made our first scientific hire. We were fortunate to near immediately connect with a very talented protein biochemist in Syracuse, who will be joining us later this month. We continue to interview in search of another entrepreneurial scientist, someone with a cell biology and gene therapy background. If you know of scientists with an interest in aging and the talent to make a difference, please do point them in our direction.
Repair Biotechnologies, Inc., a startup developing therapies with the goals of reversing atherosclerosis and atrophy of the thymus, is proud to announce it has raised a seed round from leading institutions and angel investors in the growing longevity science community, including Methuselah Foundation and others.
Founded by Reason and Bill Cherman in April 2018, Repair Biotechnologies will use these new funds to expand its foundational gene therapy development work with the addition of a recombinant protein engineering program, as it proceeds towards proof of concept results in animal models.
Additionally, Repair Biotechnologies is pleased to announce that the company has been accepted to the Grapeseed.bio incubator, recently launched by Ichor Therapeutics. The company is relocating to Upstate New York, to work hand in hand with the Ichor team towards the success of the Repair Biotechnologies development programs. Repair Biotechnologies is now hiring scientists for several positions in Lafayette, NY, just outside Syracuse.
"At Repair Biotechnologies, we are committed to developing treatments for aging and age-related diseases that address the root causes of these conditions. We are grateful for the financial support from top investors in our community, and look forward to working together with our friends at Ichor Therapeutics. We intend to draw upon their considerable experience in the field, and learn from their demonstrable success in structuring and executing challenging development programs," said Reason, CEO.
Nothing in this post should be construed as an offer to sell, or a solicitation of an offer to buy, any security or investment product. Certain information contained herein may contains statements, estimates and projections that are "forward-looking statements." All statements other than statements of historical fact in this post are forward-looking statements and include statements and assumptions relating to: plans and objectives of Repair Biotechnologies' management for future operations or economic performance; conclusions and projections about current and future economic and political trends and conditions; and projected financial results and results of operations. These statements can generally be identified by the use of forward-looking terminology including "may," "believe," "will," "expect," "anticipate," "estimate," "continue", "rankings" or other similar words. Repair Biotechnologies does not make any representations or warranties (express or implied) about the accuracy of such forward-looking statements. Accordingly, you should not place reliance on any forward-looking statements.
Decellularized Lungs Successfully Transplanted in Pigs
Researchers recently reported initial success in a transplant of decellularized lungs in pigs, though there is still a way to go in order to prove the ability to produce a completely functional lung in this way. In the decellularization process, donor lungs are stripped of their cells, leaving behind the extracellular matrix and its chemical cues for cell growth. The lung is then repopulated with cells derived from samples taken from the eventual recipient of the transplant. This minimizes the risk of transplant rejection.
Decellularization is a short-cut technology, a way to work around the present inability to produce sufficiently structured and chemically correct scaffolds for tissue engineering of complex organs. It will allow for a higher fraction of donor organs to be transplanted than is currently the case, make the logistics of organ transplant somewhat easier, as decellularized tissue is much more amenable to longer term storage, and also opens the door for the development of viable xenotransplantation, such as from pigs to humans.
Researchers have transplanted bioengineered lungs into pigs successfully for the first time. The team harvested lungs from dead pigs to construct a scaffold for the bioengineered lung to hold fast to. They used a solution of soap and sugar to wear away all the cells of the lungs, leaving behind only collagen, a protein that forms the support structure of the organ. Next, they removed one lung from every recipient pig, and used cells from those lungs, together with the collagen scaffold, growth factors, and media, to grow a new lung in a bioreactor. After a month, the lungs were transplanted into the recipient pigs.
As the cells came from the same animal that then received a bioengineered lung, there was no organ rejection. The researchers euthanized the recipient animals and tested their lungs 10 hours, two weeks, and one and two months following transplantation. The team found that before the pigs were euthanized, the transplanted lungs developed without any outside help, building blood vessels they needed for survival. However, even the two-month-old transplanted lung, while not showing any fluid collection that would indicate an underdeveloped organ, had not developed enough to independently supply the animal with oxygen. The researchers hope that bioengineered lung transplants will be feasible in humans within a decade. But first the team will "need to prove that the animals can survive on the oxygen provided by the engineered lung alone."
Attempts Continue to Link Blood Group to Natural Variations in Longevity
If we are to judge from the findings of genetic association studies, natural variation in human longevity occurs due to countless distinct factors, each of which provides a small contribution, is highly dependent on environmental circumstances, and is highly linked to other factors. Scientists have struggled to replicate more than a few known associations across different study populations, and those that have been replicated between study groups have small effects.
Blood group is genetically determined, and data on patient blood group is included in many of the data sets that report on disease incidence and mortality. A number of research groups have attempted to find robust associations between blood group and longevity, but on the whole the results seem fairly nebulous to date. Blood group B in particular keeps showing in correlations, but as an association for either longevity or a shorter life expectancy, depending on the study. That suggests that there is no useful underlying association that might be universally applied and, as is the case for the broader study of genetics and longevity, different patient populations have quite different characteristics.
The ABO blood group polymorphism has been associated with different diseases, cancer included. The cancer developments are variegated processes associated with aging. Protection from cancer and atherosclerosis is the main longevity reason. Long-survivors are an important group for the evaluation of genetic markers in cancer pathogenesis. Population studies have demonstrated that the ABO group phenotypes frequencies vary widely from one ethnicity to another.
The ABO genes control the expression of part of the carbohydrates by the epithelial cells in the respiratory, genitourinary, and gastrointestinal systems; the carbohydrate variability acts as a potential receptor for non-pathogenic and pathogenic microorganisms influencing immune responses. The first report on the relation between the ABO blood group and cancer indicated the A blood group to increase the risk of stomach cancer, while the O blood type was protective. Thereafter, the correlation between the ABO blood type and other malignancies, such as gastric and pancreatic, has been continuously reported. A total of 1.6 million healthy blood donors were followed in Denmark and Sweden: the A, B and AB blood groups were associated either with the increased or decreased risk of cancer at 13 anatomical sites as compared with the O blood group. Multiple mechanisms have been indicated to explain the blood type role in cancer progression, including altered immune response, inflammation, and cellular adhesion.
The role of the specific genetic differences contributing to life expectancy is hardly known. Several genome sequencing and GWAS studies compared the total number of disease variants in centenarians and controls, indicating that there are some evidences that centenarians harbor the anti-aging polymorphisms which protect them from diseases, although long-survivors may show numerous disease variants at a rate similar to normal people, but they are protected from their effects. The single nucleotide polymorphism defining the most common allele responsible for the O blood group is related with longevity; the centenarians are more likely than controls to have the O blood group.
The aim of the present study was to assess the ABO blood group polymorphism association with prostate, bladder, and kidney cancer, and longevity. The following data groups were analyzed: Prostate cancer (n=2,200), bladder cancer (n=1,530), renal cell cancer (n=2,650), oldest-old (n=166) and blood donors (n=994) groups. The data on the ABO blood type frequency and odds ratio in prostate cancer patients revealed a significantly higher blood group B frequency. A comparison of the oldest-old and blood donor groups revealed that blood group A was significantly more frequent and blood type B was significantly rarer in the oldest-olds. The results of the present study indicated that blood type B was associated with the risk of prostate and bladder cancer, and could be evaluated as a determinant in the negative assocation with longevity. Blood types O and A may be positive factors for increasing the oldest-old age likelihood.
Does Neuroplasticity Undergo Less of a Decline with Age than Thought?
"Use it or lose it" applies as much to the mind as to the body. Evidence suggests that a fair fraction of the observed loss of physical strength and fitness with age is lack of activity and training rather than inexorable processes of aging - though those inexorable processes exist, and will kill you if nothing is done about them. The situation is most likely similar for the brain. Not all of the observed loss is necessary or inevitable, even given the present lack of effective rejuvenation therapies that can address the causes of age-related neurodegeneration. Some fraction of the decline occurs because people choose to not to stretch their minds as much as they might. How large is this fraction? That is an interesting question without any precise answer at this time.
For a long time, it has been assumed that brain plasticity peaks at young age and then gradually decreases as one gets older. Interestingly, thanks to tremendous advances in medical imaging techniques for assessment of brain structure and function, mounting evidence for lifelong brain plasticity has been generated over the past years. In the context of practice-induced task learning, a key question is how brain plasticity can be optimized and this is an even more important consideration for older adults. The gold standard to elicit brain plasticity is to practice new tasks intensively and to organize the training epochs in such a way that skill learning and retention are maximized.
A critical requirement for neuroplasticity to emerge is to make the practice context sufficiently difficult for the learner. One way to challenge the environmental context is to confront learners with practicing more than one task within each practice session. More specifically, rather than performing subtasks in a sequential or blocked manner, one after the other (less challenging), one can also apply a more demanding random practice regime such that learners have to switch tasks from trial to trial during practice (more challenging). The latter condition has led to the apparent paradox that reduced performance levels are obtained during the training phase but better long-term retention and memory formation of the skill are observed at later stages as a result of more profound inter-task information processing strategies. This is generally known as 'contextual interference' (CI). Even though CI seemingly induces complication of the learning environment, it has been shown that older adults can equally cope with this increased contextual complexity as young adults do and that it benefits longer-term skill retention
Using magnetic resonance spectroscopy (MRS), we explored the neurochemical basis of the CI effect via determination of the practice-induced modulation of gamma-aminobutyric acid (GABA), i.e. the chief inhibitory neurotransmitter that also plays a major role in brain plasticity. We found that the MRS data demonstrated a training-induced decrease in occipital GABA level during random practice but an increased GABA level during blocked practice and this effect was even more pronounced in older adults. First, the data suggest that older adults can indeed cope with more complex random practice contexts that challenge their instantaneous performance but boost their learning potential and skill retention. Second, training-induced modulations in GABA appear to be a function of degree of contextual challenge and this effect is even amplified by aging. This modulatory capability is preserved in spite of the fact that initial GABA levels were lower in older as compared to young adults.
These data provide additional confirmation for task-training induced lifelong plasticity. New motor and other skills can be acquired at any age even though the progress may be somewhat attenuated in older as compared to young populations. In view of the demographic evolution of society, characterized by a steadily increasing proportion of older adults, the evidenced lifelong brain plasticity provides a critical foundation for a sustained role of older adults in society and for securing prolonged functional independence and quality of life.
If Life is Good, Why So Eager to Set a Schedule to Leave it Behind?
One of the small paradoxes of aging is that older people are on balance more satisfied with this business of being alive, despite suffering a growing burden of the consequences of degeneration. A related paradox is that most people, if asked, will say that they want to age, decline, and die on the same schedule as their parents and grandparents. It is possibly the case that we humans are just not very good at the important things, the ideas and decisions that really matter. Conformity is more important than life. We readily sabotage the person that we will be a decade from now. Progress happens by accident, and we collectively random walk towards an incrementally better world because we are collectively incapable of taking the logical, direct path - whether that is towards an end to violence, an end to suffering, or an end to aging.
Ask people if they would like to live longer, perhaps even much longer, so that they could have more time. Initially, they'll say that the problem is quality, not quantity. Once you've convinced them to focus only on the benefits, you're bound to still face some skepticism. Nearly everyone grew up in a cultural context in which the fact that human life is limited is depicted as a blessing in disguise. There really isn't any proof, or even convincing evidence, that living longer than we do now would wind up being demotivating or boring, yet it's something that people commonly believe.
As avid a lover of life as I am, there are dull moments, moments that I'd rather forget, moments that don't count at all, and moments at which I'd rather lie down and slack off than "live to the fullest". I am okay with that, because life is made of ups and downs. We've got needs that periodically require taking care of. That's why you don't want a party to last forever; after a while, you need quiet and privacy. Later on, you'll feel more social again. This is the point at which people are likely to draw a false analogy and say that life is just like that party: at some point, you'll want to leave.
Life should be enjoyed. This doesn't mean that you should expect to be hyped all the time, but if you have a choice between enjoying any given moment and hating it fiercely, why not the former? If you can maximize your own enjoyment without harming anyone, why not? That's something to think about in general and something that people who are skeptical about life extension should ask themselves. Being sick hardly helps you enjoy yourself; so, if you want to maximize your enjoyment, you want to stay disease-free as much as possible. This is the point at which people need to understand that elimination of disease and life extension are one and the same: you can't really have one without the other.
As life extension technologies would likely allow us to live much longer, they would allow us to maximize our enjoyment by maximizing its duration; of course, this is only a possibility, as your enjoyment of your extra time depends very much on what you do with it. This is the point at which another objection is likely to be brought up: Are the extra years granted by life extension going to be more of the same old stuff? I don't have the foggiest clue, because it depends upon a number of unknown factors, one of which is you. If you're afraid that you'll spend your additional years doing the same old boring job, I'd say that you've got a problem with your job, not with life extension.
Hydrogen Sulfide Influences Cellular Senescence via Splicing Mechanisms
In this open access paper, researchers report that compounds delivering hydrogen sulfide into cells slow the pace at which those cells become senescent in culture. The mechanisms involved are not fully explored but involve splicing factors, proteins that have a strong influence over gene expression. As the biochemistry of cellular senescence is explored, and researchers find ways to potentially hold back the transition of cells into the senescent state, we might ask whether or not this is a good idea. Lingering cellular senescence is a cause of aging, but most cells become senescent for a good reason - they are damaged, potentially cancerous, have replicated too many times for continued safety, or the surrounding environment is toxic. Most self-destruct rather than remaining to contribute to the aging process.
Will it be helpful rather than harmful to prevent senescence? Current approaches to senescent cells involve destroying them, which seems the better path forward. Cells that become senescent are not, on balance, the sort of cell that one would want to keep around. Better to remove them, I think. So how to interpret the evidence here regarding the influence of hydrogen sulfide on cellular senescence and aging in general? It seems positive and also suppresses cellular senescence. What does it actually achieve under the hood, what is the full balance of relevant mechanisms? It is perhaps a little early to say, and we should continue to watch the accumulation of evidence on this topic.
The biochemical and functional pathways most dysregulated by age in the human peripheral blood transcriptome are enriched for transcripts encoding the regulatory machinery that governs splice site choice. Changes in splicing regulation have also been linked with lifespan in both mammalian and invertebrate model systems. Evidence that these changes are functional is provided by the observation that large-scale dysregulation of patterns of alternative splicing is characteristic of many age related diseases.
The accumulation of senescent cells is emerging as an important driving factor of the ageing process in multiple species. Senescent cells do not divide, are viable and metabolically active, but have altered physiology. This includes the secretion of the SASP, a cocktail of pro-inflammatory cytokines and tissue remodelling factors that induces senescence in neighbouring cells in a paracrine manner. Senescent cells also show dysregulation of splicing regulator expression in vitro, and restoration of splicing factor expression to levels comparable with those seen in younger cells has recently been demonstrated to be associated with reversal of multiple senescence phenotypes in senescent human primary fibroblasts.
There is now enormous interest in compounds with the potential to kill senescent cells or ameliorate their effects. The endogenous gaseous mediator hydrogen sulfide (H2S) has been described to exert a protective effect against cellular senescence and ageing phenotypes, and accordingly, to have protective effects against several age related diseases, although many of these studies have been carried out using non-physiological conditions, using very high levels of H2S. Plasma H2S level declines with age, is associated with hypertension in animals and humans and shows a significant inverse correlation with severity of coronary heart disease.
Here, we aimed to assess the effect of the H2S donor Na-GYY4137, and since mitochondria are a source and a target of H2S, three novel H2S donors, AP39, AP123, and RT01 previously demonstrated to be targeted specifically to the mitochondria, on splicing regulatory factor expression and cell senescence phenotypes in senescent primary human endothelial cells. Treatment with Na-GYY4137 resulted in an almost global upregulation of splicing factor expression in treated cells. Conversely, H2S donors targeted to the mitochondria also resulted in rescue from senescence but each demonstrated a very specific upregulation of transcripts encoding the splicing activator protein SRSF2 and the splicing inhibitor protein HNRNPD.
Abolition of either SRSF2 or HNRNPD expression in primary endothelial cells in the absence of any treatment resulted in increased levels of cellular senescence. None of the H2S donors were able to reduce senescent cell load in cells in which SRSF2 or HNRNPD expression had been abrogated. These data strongly suggest that mitochondria-targeted H2S is capable of rescuing senescence phenotypes in endothelial cells through mechanisms that specifically involve SRSF2 and HNRNPD.
Removing Tau Enhances Brain Function in Young Mice
Aggregation of altered tau protein is arguably the primary cause of brain cell death in the late stages of Alzheimer's disease. It is quite fundamental in cells, involved in maintaining the cytoskeletal structure of microtubules, but nonetheless can be removed without any great disruption of function - though the evidence is mixed on whether that means no unwanted side-effects. This approach has been tried in mice altered to generate similar pathology to that of human Alzheimer's disease. Researchers here instead examine the outcome of removing tau in young mice and find that it actually improves the metabolism of the brain and measures of cognitive function. Mice are not humans, but perhaps it is the case that we might all be enhanced by some form of therapy that can greatly reduce levels of tau in the brain, and not just through a greater ability to resist the onset of age-related neurodegeneration.
Tau is a protein that associates with microtubules and is found prominently in the axons of neurons. Abnormal modifications of tau are involved in a number of neurodegenerative diseases, known as tauopathies, which are characterized by the formation of pathological deposits of tau. Hyperphosphorylated or cleaved forms of tau are the principal components of neurofibrillary tangles, one of the neuropathological hallmarks of Alzheimer's disease (AD). Pathological forms of tau generate serious alterations in neuronal activity, affecting synaptic transmission and learning and memory processes, which finally leads to neurodegeneration.
Genetic deletion of tau could be protective. Studies in a mouse model of AD have shown that ablation of tau expression prevents neurotoxicity induced by the amyloid-β peptide and improves cognitive damage. Similarly, tau deletion protects against the effects of stress on neuronal structure and working memory. However, other reports suggest that the absence of tau could have a negative effect on normal brain function.
Pathological forms of tau can impair mitochondrial function, including mitochondrial morphology, transport, and bioenergetics. Interestingly, we found that the expression of pathological tau species, in particular truncated tau, induces mitochondrial fragmentation and bioenergetics failure in neurons. Similarly, phosphorylated tau induces mitochondrial fragmentation and affects the bioenergetics function of mature neurons. Thus, the absence of tau protein in neural cells could prevent the effects on mitochondrial structure and function produced by post-translationally-modified tau.
Considering that limited research has used tau-deficient mouse models and the role of tau on the regulation of mitochondrial function and the resulting implications on cellular and cognitive processes are not entirely clear, a study examining the impact of tau ablation will contribute to the understanding of the physiological function of tau protein in vivo. The present study was conducted in litters of young mice (3 months old) to investigate the effects of tau reduction in hippocampal tissue, to identify the implications of tau on mitochondrial function and behavior during youth.
Our results showed that tau deletion had positive effects on hippocampal cells by decreasing oxidative damage, favoring a mitochondrial pro-fusion state, and inhibiting mitochondrial permeability transition pore (mPTP) formation by reducing cyclophilin D (Cyp-D) protein. More importantly, tau deletion increased ATP production and improved the recognition memory and attentive capacity of juvenile mice. Therefore, the absence of tau enhanced brain function by improving mitochondrial health, which supplied more energy to the synapses. Thus, our work opens the possibility that preventing negative tau modifications could enhance brain function through the improvement of mitochondrial health.
Autophagic Flux Does Not Decline with Age in Dermal Fibroblasts
Autophagy is a collection of cellular maintenance processes that recycle damaged or unwanted proteins and structures. It is generally considered to become less effective with age, and that this decline is an important aspect of aging, but nothing is simple in cellular biochemistry. For any well supported topic there are always exceptions and there is always at least some opposing evidence. Here, researchers report on data that shows autophagy to be just as active in old dermal fibroblasts as it is in the younger versions of such cells. It is hard to say what to make of that, given the sizable weight of all of the existing evidence for age-related dysfunction in autophagy, whether taken as a whole, or examining specific subsystems vital to the overall process.
Autophagy is an intracellular stress response that is enhanced under starvation conditions, and also when the cellular components are damaged. Aging accompanies an increase in intracellular stress and has significant impact on the skin. Since dermal fibroblasts are a powerful indicator of skin aging, we compared the autophagic activity of human skin fibroblasts between the young and old. The number of autophagosomes per cytoplasmic area was similar between young and aged fibroblasts. The amount of LC3-II, a form associated with autophagic vacuolar membranes, was also similar between the groups. Although residual bodies were more common in aged dermal fibroblasts, LC3 turnover and p62 assay showed little difference in the rate of lysosomal proteolysis between the young and old. RNA-seq analysis revealed that the major autophagy-modulating genes were not differentially expressed with age.
Our results suggest that the basal autophagic flux in aged dermal fibroblasts is largely comparable to that of young fibroblasts. However, with a higher speed and amount of waste production in aged cells, we postulate that such autophagic flux may not be sufficient in keeping the old cells "clean", resulting in skin aging. Aging is a complex process and, as such, the relationship between autophagy and aging is not straightforward. That is to say, autophagy does not simply decline with age. Regardless of the controversies on autophagic activity with age, autophagy plays a crucial role in counteracting aging, and strategies aimed at its modulation should hold promise for the prevention of skin aging.
A Review of Neurogenesis in the Aging Brain
Neurogenesis is the process by which new neurons are created and then integrated into existing neural circuits. Does neurogenesis take place in the adult human brain? That is once again a subject for debate after two decades of consensus, with the arrival of solid evidence for the absence of neurogenesis in adult humans, even as other researchers continue to produce data showing that it does take place. This newfound uncertainty contrasts with the well-established presence of neurogenesis in adult mice, the species that is the focus of the vast majority of research on this topic.
This an important topic. Along with synaptic plasticity, it determines the ability of the brain to repair itself, to recover from the variety of losses that occur with aging or injury. If neurogenesis does occur in adult humans, then there may be comparatively straightforward approaches that can boost the operation of this process in order to slow the impact of aging. If it does not occur in adult humans, then the prospect of repairing the aging brain becomes harder and more distant.
The main reason behind the continuing interest in understanding the process of mammalian adult neurogenesis is the notion that similar processes might be involved in the human brain. Whether neurogenesis in humans exists has been investigated using several and distinct approaches that brought compelling evidence about the presence of adult hippocampal neurogenesis in human brains. Interestingly, two very recent - but opposing - publications brought back the debate concerning the existence of human adult neurogenesis. The first, using postmortem and fresh tissue, reported that there was no evidence of neurogenesis in humans after adolescence whatsoever, while the second demonstrated the exact opposite by showing that adult neurogenesis persists during life in humans, albeit with a small decrease with aging. Further exploration of this complex question is necessary in order to conclude on the processes underlying the timeline and the mechanisms of neurogenesis in humans.
Recently, in addition to the study of the overall process of neurogenesis, much effort has focused on deciphering the intrinsic regulation of stem cells in the brain, both in the hippocampus as well as the subventricular zone (SVZ) niche. Aging negatively affects neurogenesis by inducing a sharp and continuous decrease in cell production in both the SVZ and hippocampal neurogenic niches of the brain. With aging, activated neural stem cells (NSCs) lose their proliferative potential and become quiescent, but, remarkably, they can be reactivated to a certain extent upon stimulation, such as exercise or even seizure, indicating that NSC plasticity is preserved to a certain extent in the aged organism.
Because of the enormous consequences of aging on NSCs, a lot of effort has focused on identifying mechanisms that could potentially reset the aging clock. Systemic manipulations such as exercise, calorie restriction, and heterochronic blood transfer have demonstrated that it is possible to reactivate the intrinsic program in order to rejuvenate NSCs and, consequently, the brain. The delicate balance between NSC quiescence and activation is easily shifted depending on the different stimuli and could be used to better manipulate NSC fate in vitro and in vivo. Moreover, recent findings point to the conclusion that aging is not necessarily a permanent state, but could be malleable, and that finding ways to interfere in the cell intrinsic machinery in order to slow down or even reverse this process will be the challenge for years to come.
Juvenesence Expands its Support of AgeX Therapeutics
Juvenescence is one of the more recent venture groups to become enthusiastically involved in supporting the development of means to treat aging, and the organization's principals are now beginning to build their positions in earnest. As this unfolds, we obtain insight into their interpretation of the field of longevity science, the lines of development that they believe to be plausible and interesting. The founding members have expressed a strong interest in SENS rejuvenation research programs, but will they follow up with the investments to match? It always seems impolite to ask that question, but our community has been disappointed in the past.
You might recall that Juvenescence invested in AgeX Therapeutics not so long ago. AgeX aims to build out an platform that is intended as an incremental advance over present approaches to regenerative medicine, mixing in telomerase upregulation with the production and deployment of cell therapies. Juvenescence has now expanded their support of AgeX Therapeutics. It will be interesting to see how this line of work matures, and whether the AgeX staff choose to explore some of the surprising outcomes that are emerging from the induced pluripotency field these days, particularly those resulting from inducing pluripotency in vivo - something that sounds like a terrible idea, but has in fact produced initially intriguing results in mice.
BioTime, Inc., a clinical-stage biotechnology company focused on degenerative diseases, today announced a new strategic alignment between AgeX Therapeutics and Juvenescence Limited, a global leader in developing therapeutics focused on improving and extending human lifespans. Under the terms of the agreement, Juvenescence will purchase, in a single transaction, 14.4 million shares of AgeX Therapeutics from BioTime for 43.2 million. "We feel it is a great fit with the Juvenescence team of drug developers and scientists. First and foremost, we look forward to developing and bringing products to the patients as novel treatments to potentially offset some of the maladies of getting old."
AgeX Therapeutics, Inc., a subsidiary of BioTime, Inc., is a biotechnology company focused on the development of novel therapeutics for age-related degenerative disease. The company's mission is to apply the proprietary technology platform related to telomerase-mediated cell immortality and regenerative biology to address a broad range of diseases of aging. The products under development include two cell-based therapies derived from telomerase-positive pluripotent stem cells and two product candidates derived from the company's proprietary induced Tissue Regeneration (iTR) technology.
AGEX-BAT1 and AGEX-VASC1 are cell-based therapies in the preclinical stage of development comprised of young regenerative cells designed to correct metabolic imbalances in aging and to restore vascular support in ischemic tissues respectively. AGEX-iTR1547 is a drug-based formulation in preclinical development intended to restore regenerative potential in a wide array of aged tissues afflicted with degenerative disease using the company's proprietary iTR technology. Renelon is a first-generation iTR product designed to promote scarless tissue repair which the Company plans to initially develop as a topically-administered device.
Theorizing that Adult Neurogenesis is Linked to Olfactory Function
Neurogenesis is the production and integration of new neurons into neural networks in the brain. Along with synaptic plasticity, it determines the ability of the brain to recover from damage. There is some controversy over the degree to which it occurs in adult humans; the consensus is that it does, but the vast majority of research on this topic has been carried out in mice, not humans. If there is little or no natural neurogenesis in the adult human brain, a situation quite different from that of mice, then the prospects diminish for the development of therapies to hold back aging that work by increasing neurogenesis. This is an important topic in the field of regenenerative research.
The open access paper noted here offers an interesting hypothesis: that humans and a range of other larger-brained mammals exhibit lesser (or possibly absent) adult neurogenesis because they have lost olfactory function over evolutionary time. We should consider adult neurogenesis to be a co-evolved feature of large and capable olfactory systems in the brain, and we do not have a large and capable olfactory system. Mice do. This is a tenuous hypothesis, in need of considerable support, but it is worth thinking over for a few moments.
The majority of mammals show adult hippocampal neurogenesis to some extent, with exceptions in dolphins, humans, and some bats. Neurogenesis seems to be under selective pressure. Under an evolutionary profile, humans have it during the youngest ages that likely had the greatest phylogenetic importance in the past. Open questions about adult human neurogenesis include: (i) are low levels of neurogenesis functionally relevant? (ii) are there vestigial/quiescent remnants of stem cell niches and can these be reactivated in some way? Some authors, considering that the new neurons within the dentate gyrus, even a low number, can be highly functional (at least in animal models), argue that "there has been evolution toward neurogenesis-based plasticity rather than away from it". At present, no systematic, fully comparable studies are available on a wide range of mammalian species to support this view.
The most likely explanation for the general reduction of adult neurogenesis in humans when compared to rodents might be related to the reduced importance of specific brain functions linked to survival, replaced by other (higher) cognitive functions. This potential explanation acquires relevance when olfaction/olfactory brain structures, such as subventricular zone (SVZ) neurogenesis, are concerned. Although olfaction in humans is considered more impactful than previously thought (in term of total amount of neurons), the relative size of the olfactory bulb with respect to the whole brain volume (0.01% of the human brain compared to 2% of the mouse brain) and the importance of olfaction for survival are quite reduced when compared to rodents.
Dolphins are large-brained mammals. Among several aspects worthy of a comparative study on neurogenic activity in dolphins, we focused on a unique trait: the absence of olfaction/olfactory brain structures. We recently expressly searched the periventricular region of dolphins for neurogenic processes. The persistence of a vestigial remnant (functionally inactive) of the SVZ neurogenic niche in dolphins strongly suggests that periventricular neurogenesis reduction or disappearance occurs in parallel with reduction or disappearance of olfactory brain structures across evolution.
In conclusion, three features of adult neurogenesis are crucial when considering its translational value: (i) its substantial decrease in humans and other long-living, large-brained mammals; (ii) its decrease with the age of the individuals (in both SVZ and hippocampus); and (iii) a scarce propensity/efficacy for lesion-induced repair in mammals. These constraints seem to strongly depend on evolutionary pathways. Evolution drives the occurrence, rate, and type of plasticity among mammals, and interspecies differences must be taken into account when translating results from mice to humans.