The Aged Bone Marrow Niche Impedes Hematopoietic Stem Cell Function

Stem cell activity declines with age for a variety of reasons. Damage in the stem cells, damage in the supporting cells of the stem cell niche, as well as altered behavior in stem cells and niche cells, a reaction to signaling changes such as increased inflammation. In some populations, such as muscle stem cells, the evidence suggests that reactions to signaling are a much more important factor than intrinsic damage. Those stem cells can in principle be put back to work in an aged individual. For hematopoietic stem cells, responsible for generating blood and the immune system, the evidence is less clear. In very late life it has been shown that these cells are very damaged, but it remains to be determined as to whether the majority of the problem is damage or reactions to signaling in earlier old age.

Given this, more research such as the work noted here is needed to better understand the aging of this vital stem cell population and its niche. The nature of this age-related decline determines which approaches to rejuvenation are more likely to work. The data here suggest that delivering new, replacement hematopoietic stem cells will be impeded by changes and damage in the aged stem cell niche. The niche is a sufficiently important determinant of function to require attention.

Aged bone marrow niche impedes function of rejuvenated hematopoietic stem cells

A new study shows that the youthful function of rejuvenated HSCs upon transplantation depends in part on a young bone marrow "niche," which is the microenvironment surrounding stem cells that interacts with them to regulate their fate. "The information revealed by our study tells us that the influence of this niche needs to be considered in approaches to rejuvenate old HSCs for treating aging-associated leukemia or immune remodeling."

Old HSCs exhibit a reduced reconstitution potential and other negative aspects such as altered gene expression profiles and an increase in a polar distribution of proteins. (Polarity is believed to be particularly important to fate decisions on stem cell division and for maintaining an HSC's interaction with its niche. Consequently, a failure to establish or regulate stem cell polarity might result in disease or tissue deterioration.) Aging of HSCs might even affect lifespan. Researchers already knew that increased activity of a protein called Cdc42, which controls cell division, leads to HSC aging, and that when old HSCs are treated ex vivo with CASIN, an inhibitor of Cdc42 activity, they stay rejuvenated upon transplantation into young recipients. The aim of this latest study was to learn what happens to these rejuvenated HSCs when they are transplanted into an aged niche.

Researchers transplanted rejuvenated aged HSCs into three groups of mice: young (8 to 10 weeks old), old (19 to 24 months old) and young cytokine osteopontin (OPN) knockout mice (8 to 12 weeks old). The team had recently demonstrated that a decrease in the level of secreted OPN in the aged bone marrow niche confers hallmarks of aging on young HSCs, and also that secreted OPN regulates HSC polarity. Old HSC and rejuvenated old HSCs were therefore transplanted into the OPN knockout recipients to test whether a lack of this protein in the niche affects the function of old rejuvenated HSCs. The results were then analyzed for up to 23 weeks after transplantation."They showed us that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of OPN found in aged niches. This tells us that in order to sustain the function of rejuvenated aged HSCs, we will likely need to address the influence of an aged niche on rejuvenated HSCs."

An aged bone marrow niche restrains rejuvenated hematopoietic stem cells

Aging-associated leukemia and aging-associated immune remodeling are in part caused by aging of hematopoietic stem cells (HSCs). An increase in the activity of the small RhoGTPase cell division control protein 42 (Cdc42) within HSCs causes aging of HSCs. Old HSCs, treated ex vivo with a specific inhibitor of Cdc42 activity termed CASIN, stay rejuvenated upon transplantation into young recipients. We determined in this study the influence of an aged niche on the function of ex vivo rejuvenated old HSCs, as the relative contribution of HSCs intrinsic mechanisms vs extrinsic mechanisms (niche) for aging of HSCs still remain unknown. Our results show that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of the cytokine osteopontin found in aged niches. The data imply that sustainable rejuvenation of the function of aged HSCs in vivo will need to address the influence of an aged niche on rejuvenated HSCs.

Hypertension Alters Artery Structure, Accelerating the Development of Atherosclerosis

The raised blood pressure of hypertension is well known to accelerate the progression of atherosclerosis. It certainly makes it more likely for blood vessels weakened by atherosclerotic lesions to rupture, or for the lesions themselves to fragment and cause blockages. Beyond that, however, mechanisms are at work in the environment of high blood pressure to accelerate the growth of these lesions. The major consequences of atherosclerosis, stroke and heart attack, are the cause of death for a sizable fraction of all people, and this is why blood pressure control produces a meaningful reduction in mortality risk, by slowing the progression towards those consequences.

Blood pressure-lowering drugs are routinely used to prevent the development of atherosclerosis and heart disease, but the mechanism of this effect is still unknown. People suffering from high blood pressure (hypertension) often have accompanying changes in the hormones that control blood pressure and it has been unclear whether the pressure itself or the hormonal changes are the driver of accelerated atherosclerosis. To investigate this, researchers analyzed the development of atherosclerosis in minipigs that were genetically engineered to have high blood cholesterol and develop atherosclerosis.

Minipigs have arteries that are very similar in structure to human arteries and like humans they develop atherosclerosis in the heart when exposed to high blood cholesterol. By manipulating blood pressure in the pigs and by analyzing the effects on arteries in the heart, the researchers found that the direct forces of pressure on arteries leads to structural changes that facilitate the development of atherosclerosis. "Arteries become denser and allow less passage of molecules from the blood. This includes the LDL particles that carry blood cholesterol, which instead accumulate in the innermost layer of arteries, where they drive the development of atherosclerosis."

This finding uncovers an intimate relationship between the most important risk factors for atherosclerosis, LDL cholesterol and high blood pressure. While it has been known for decades that accumulation of LDL particles in arteries lead to atherosclerosis, the new research shows that high blood pressure accelerates the accumulation of LDL. Therefore, high blood pressure aggravates the effect of having high LDL cholesterol in the blood.


Neutrophils May Be Involved in the Transmission of Cellular Senescence in Aged Tissues

Researchers here provide evidence suggesting that one of the mechanisms by which senescent cells encourage nearby cells to also become senescent is via recruitment of neutrophil cells, a somewhat more complicated process than the direct signaling investigated to date. In its role as a suppressor of cancer, it makes sense for the state of cellular senescence to be transmissible to nearby cells, as that raises the chances of successfully preventing cancer from arising in a localized environment of cell damage. In aging, it makes things worse, however. Excessive numbers of lingering senescent cells cause harm to their surroundings and make that harm worse over time via the creation of yet more senescent cells.

The immune system is a collection of cells and proteins that works to keep the body healthy. But it's a balancing act. Tip in one direction and an infection might cause organ damage or lead to sepsis. Overbalance in the other and the cure might lead to an autoimmune disease. Neutrophils are a key part of immune system action. They help healing by clearing out cellular debris after an infection. They're also armed and can kill microbes. During infection, neutrophils release a short blast of unstable molecules called reactive oxygen species.

Another way the immune system keeps the body healthy is by telling damaged cells to perish. But not all cells die. Cells told to close down by the body sometime ignore that signal. Instead, they live in a sort of zombie state, undead but spewing toxic chemicals. These cells are senescent cells. They damage their neighbors through release of a toxic protein stew.

Researchers examined neutrophils' effect on human and mouse cell senescence. They co-cultured neutrophils with human cells and depleted neutrophils in mice to determine their role in encouraging senescence. "We asked if neutrophils could be drivers of cellular senescence in tissues and contribute to aging. We found that neutrophils can cause senescence in neighboring non-immune cells by damaging their telomeres via reactive oxygen species. We also found that if we deplete neutrophils in mice, we can prevent telomere damage and senescence. Our study suggests an evolutionary trade-off between having a good working immune system and age-related pathology. While neutrophils have evolved to play important roles in fighting infection, they may contribute to collateral damage and induction of cellular senescence which will be detrimental later in life."


Calorie Restriction as an Adjuvant Cancer Treatment

Calorie restriction and intermittent fasting have been extensively studied in the context of aging, and most of the age-slowing interventions so far tested in animal studies are derived in some way from a knowledge of the stress response mechanisms triggered by a lowered calorie intake. The long term effects of calorie restriction and fasting in short-lived species are quite different from those in long-lived species: only the short-lived species exhibit a meaningful extension of life span, as much as 40% in mice. Yet the short-term effects on metabolism and cellular mechanisms are very similar. The beneficial response to periods of low nutrient availability evolved very early in the development of life, likely because it increases the chance of living to replicate in the next period of abundance.

The short-term effects of calorie restriction are beneficial to normal cells, but harmful to cancer cells. Calorie restriction upregulates cell maintenance mechanisms likely to cause cancer cells to self-destruct. This is now well known, demonstrated in animal models and human trials. In recent years researchers have put considerable effort into codifying and quantifying fasting and fasting mimicking diets in the context of cancer treatment. Similarly, there is considerable interest in the application to cancer treatment of calorie restriction mimetic drugs, those that induce some fraction of the response to lowered calorie intake. An example is the class of mTOR inhibitors, known to slow aging and lower cancer incidence in mice.

Metabolic Reprogramming by Reduced Calorie Intake or Pharmacological Caloric Restriction Mimetics for Improved Cancer Immunotherapy

Fasting and caloric restriction (CR) were shown in non-human primates to reduce the incidence of not only cancer but also metabolic diseases, arteriosclerosis, and neurodegeneration - thus extending the healthspan. Furthermore, fasting and CR were shown in yeast, plants, worms, flies, and rodents to prolong lifespan and reduce the incidence of a wide array of age-associated pathologies, notably malignant diseases. Fasting-mimicking-diets (FMDs) reproduce the effects of fasting while maintaining a food supply, yet with a limited number of calories and a particular macronutrient composition, frequently poor in proteins, enriched in unsaturated fats, and with low to moderate proportions of carbohydrates. FMDs were shown in pilot trials to reduce risk factors associated with aging, diabetes, cardiovascular disease, and cancer, without major adverse effects. In this review, when indistinctively referring to fasting, CR, and/or their mimetics, we will use the term "energy reduction" (ER).

It has been known for more than a decade that starvation protects normal but not transformed cells against chemotherapeutics and oxidative damage, in yeasts, cell cultures, and mice. This effect has been observed in several malignancies such as colon carcinomas, melanomas, gliomas, and breast cancers. Such phenomenon has been dubbed "differential stress resistance" (DSR; sometimes referred to as "differential stress sensitization"). DSR likely originates from the independence of malignant cells from growth signals and their insensitivity to anti-growth signals. These characteristics result from oncogenic gain-of-function mutations affecting the activity of AKT, mechanistic target of rapamycin (mTOR), RAS, and other pro-proliferative signaling factors, and/or of loss-of-function mutations in genes encoding tumor suppressors such as TP53. Consequently, cancer cells are unable to adapt to the lack of nutrients and maintain a sustained proliferation. On the contrary, normal cells switch to a maintenance program conferring resistance to stress.

One of the knock-on effects of ER is autophagy induction, which is triggered in response to cellular stress such as DNA damage, endoplasmic reticulum or mitochondrial stress, oxidative or metabolic stress. In cancer cells, autophagic activity helps to survive in the hypoxic and nutrient-deprived tumor microenvironment and has also been described as a drug resistance mechanism. Somewhat counter-intuitively, this knock-on autophagy induction is not detrimental to the general antitumoral effect of ER and helps explain DSR. As we have seen, cancer cells are more sensitive to metabolic stresses and, as we know, they are also more sensitive to genotoxic stress than most somatic cells. Thus, the concomitant amplification of these two stresses thanks to ER and chemotherapy can prove fatal to malignant cells, whereas ER-induced autophagy probably contributes to its observed protective effect against chemotherapy in healthy cells.

DSR is thus mediated in part by the different metabolic requirements of cancer and healthy cells, but also - and perhaps chiefly - by the cellular effects of ER, especially as it pertains to autophagy. We have known for a few years that autophagy promotes (i) cancer cell immunogenicity, (ii) tumor-bed immune infiltration, and (iii) depletion of tumor-infiltrating regulatory T cells, especially when autophagy is induced at the same time as immunogenic cell death (ICD)-inducing agents are administered. This points towards an immune mechanism that explains the capacity of ER to prevent - and probably even to treat - cancer. This has led us and others to propose ER as an adjuvant to immunotherapy, especially as ER is relatively well tolerated.

Tau Immunotherapy for Alzheimer's Disease is Proving to be as Challenging as Amyloid Immunotherapy

Alzheimer's disease is characterized by the aggregation of first amyloid-β and then tau protein in later stages. It took many years and many attempts to produce immunotherapies capable of clearing amyloid-β from the brain, only to find that this doesn't in fact help patients to any great degree. Amyloid-β may be a side-effect of the causative mechanisms - such as infection, or chronic inflammation - or only important in the earliest stages of the development of Alzheimer's. By the time tau aggregation happens, a different disease process has become dominant. One of the next options is to target tau protein with the same sorts of immunotherapy technologies. So far this is proceeding in much the same way, with the first attempts failing to achieve meaningful levels of clearance.

With anti-amyloid antibodies now consistently hitting their target, tau immunotherapy represents the next frontier. In Alzheimer's disease, tau tangles correlate far more closely with cognitive decline than plaques do, and tau aggregates are the main pathology in many related disorders. As with amyloid, however, initial trials of anti-tau antibodies have been beset by failures. Already, several antibodies that bind the N-terminus or C-terminus of tau have been scuttled after not doing recipients any good. Meanwhile, preclinical evidence suggests that antibodies that go after the protein's mid-section, particularly its microtubule-binding region (MTBR), may be better at preventing aggregates from spreading. Several such antibodies have now entered Phase 1 or 2.

At the 15th International Conference on Alzheimer's and Parkinson's Diseases, researchers discussed a number of these programs. Roche offered a first look at biomarker data from the negative Phase 2 trial of the N-terminal-targeting antibody semorinemab. Other speakers touted MTBR-binding antibodies. Pinteon Therapeutics showed preliminary Phase 1 findings for PNT001, while the Technical University of Munich presented on UCB's beprenemab, also in Phase 1. Prothena's MTBR-binder PRX005 is still preclinical, but the company offered mechanistic data on how it might inhibit the transfer of pathological tau.

Time will tell if this newest crop can perform in the clinic. Researchers believe the field is making progress in figuring out how to target the protein, and are encouraged by cerebrospinal fluid data that link cerebrospinal fluid MTBR tau with tangles, and specific tau phospho-species with plaques. "That's really exciting for us as a field. We're learning so much more about this target."


A Worse Oral Microbiome Correlates with Some Metrics Indicating Alzheimer's Risk

There has been some evidence for the oral microbiome, particularly the harmful bacterial species responsible for gingivitis, to contribute to systemic inflammation throughout the body. This in turn raises the risk of suffering from dementia, including Alzheimer's disease. The mechanisms look plausible, but the epidemiological evidence is mixed, suggesting that this is a small contribution to overall risk. Alzheimer's is a condition characterized by a long slow buildup of amyloid, and a later and more damaging aggregation of tau protein. Researchers here find that the presence of harmful microbial species in the oral microbiome correlates with a measure of amyloid aggregation, but not with tau aggregation in older patients. This suggests perhaps a contribution to the early establishment of the condition, but not to its later progression.

Alzheimer's disease is characterized by two hallmark proteins in the brain: amyloid beta, which clumps together to form plaques and is believed to be the first protein deposited in the brain as Alzheimer's develops, and tau, which builds up in nerve cells and forms tangles. "The mechanisms by which levels of brain amyloid accumulate and are associated with Alzheimer's pathology are complex and only partially understood. The present study adds support to the understanding that proinflammatory diseases disrupt the clearance of amyloid from the brain, as retention of amyloid in the brain can be estimated from cerebrospinal fluid (CSF) levels. Amyloid changes are often observed decades before tau pathology or the symptoms of Alzheimer's disease are detected."

The researchers studied 48 healthy, cognitively normal adults ages 65 and older. Participants underwent oral examinations to collect bacterial samples from under the gumline, and lumbar puncture was used to obtain CSF in order to determine the levels of amyloid beta and tau. To estimate the brain's expression of Alzheimer's proteins, the researchers looked for lower levels of amyloid beta (which translate to higher brain amyloid levels) and higher levels of tau (which reflect higher brain tangle accumulations) in the CSF.

Analyzing the bacterial DNA of the samples taken from beneath the gumline,the researchers quantified bacteria known to be harmful to oral health (e.g. Prevotella, Porphyromonas, Fretibacterium) and pro-oral health bacteria (e.g. Corynebacterium, Actinomyces, Capnocytophaga). The results showed that individuals with an imbalance in bacteria, with a ratio favoring harmful to healthy bacteria, were more likely to have the Alzheimer's signature of reduced CSF amyloid levels, indicating low clearance and greater amyloid in brain tissue. The researchers hypothesize that because high levels of healthy bacteria help maintain bacterial balance and decrease inflammation, they may be protective against Alzheimer's. The researchers did not find an association between gum bacteria and tau levels in this study, so it remains unknown whether tau lesions will develop later or if the subjects will develop the symptoms of Alzheimer's.


It is Faintly Ridiculous to Propose that Human Life Span Cannot be Increased by Altering Metabolism

Today's open access commentary is, I think, an overreaction to present challenges in engineering greater longevity via metabolic manipulation. I would be the first to say that altering the operation of metabolism is not a good path forward, at least if the goal is to engineer greater healthy longevity in our species. Cellular metabolism and its intersection with aging is ferociously complex and poorly understood in detail. Those details matter greatly: there are many feedback loops and switches based on protein levels that will change from beneficial to harmful for reasons that only become apparent after years of painstaking research. The best-studied mechanisms that link cellular metabolism to individual and species longevity have been under investigation for decades, and are still at a point at which related interventions are haphazardly beneficial and poorly understood.

Further, those best studied mechanisms, linked to the response to calorie restriction and other stresses, cannot greatly increase life span in long-lived species. They work quite well in short-lived species. That is well demonstrated: calorie restriction itself boosts mouse life span by as much as 40%, and certainly does not do that in humans. Thus we should not be looking to altered metabolism as a path that can add decades to the healthy human life span in the foreseeable future.

Arguing that this line of development is hard, and that all of the specific approaches examined so far appear to be capable of producing only low yields at best, in terms of healthy years added, is one thing. Arguing that it is impossible to ever achieve meaningful gains via this line of development is quite another. It is ridiculous to argue that it is impossible in principle to engineer humans to be very long-lived by changing the operation of cellular metabolism. We only have to look at the wide range of life spans in mammals to note that some concrete collection of differences must be enabling naked mole-rats to live nine times as long as mice, or for whales to live for centuries. Making significantly longer-lived humans through the approach of altered cellular metabolism is scientifically plausible - it just isn't a viable project at this time, and probably won't be for a lifetime yet.

This is why many people who have looked into the field in detail support the damage repair approach to rejuvenation, as first put forward by Aubrey de Grey and presently championed by the SENS Research Foundation and its network of allies and researchers. This is explicitly a strategy to work around the inability to make near term progress in altering metabolism. Instead we keep the metabolism we have, and target the periodic elimination of the various well-described forms of cell and tissue damage that cause aging. Remove the damage, and rejuvenation results, as illustrated in animal studies in which senescent cells are selectively destroyed via senolytic therapies.

The Zugzwang Hypothesis: Why Human Lifespan Cannot Be Increased

Lifespan is one of the most variable life history traits in the animal kingdom, lasting from days to centuries. Despite intensive investigation, there are still many grey areas in our understanding of the factors which contribute to the variability of lifespan. Humans are among the fortunate animals which have an unusually long lifespan compared to their similar sized mammals. On the flip side, the long lifespan of humans and large genetic heterogeneity are important reasons why it is very difficult to use humans as models to study ageing or longevity or test the efficacy of anti-ageing interventions. Ageing studies on humans often require a very large cohort of people and can potentially be affected by many confounding factors. As a consequence, most studies involving ageing, lifespan, and anti-ageing interventions are based on model systems.

In the evolutionary history after divergence from the great apes, the most recent of our primate ancestors, humans have completed almost 300,000 generations. During this period, the lifespan of H. sapiens has almost doubled. The increased longevity of humans is, in part, attributable to environmental changes; improved food, water, and hygiene; reduced impact of infectious disease; and improved medical care at all ages. However, the above factors had an opportunity to play some role in increasing lifespan only in the last 2 centuries. The dramatic increase in human lifespan compared to our nearest ancestors, should, therefore, must have other valid explanations. It is highly conceivable that forces of natural selection may have played vital role in increasing the basic longevity of humans.

Zugzwang is a German word with the literal meaning "compulsion to move." This word is frequently used in chess to describe a situation when a player gets a disadvantage because it is his turn to play, but all the available moves are bad. In Zugzwang position, any move the player makes will clearly weaken his position. Here, I propose that at this stage of evolution, humans may face the Zugzwang problem. Scientific research and the understanding of the hallmarks of ageing now provide humans with more than a dream to extend lifespan. However, it must be taken into consideration that natural selection has already played its part in extending human lifespan much beyond the expectation. All possible mechanisms which can increase longevity in lower animals have already been exploited by natural selection to stretch human lifespan. Any artificial attempt to tinker, through any possible intervention, with the signalling pathways or transcription factors to achieve a longer lifespan may actually be disadvantageous to humans.

Humans may thus be considered to be in the Zugzwang state. Humans may have already achieved or approached the maximum life­span, and further lifespan extension may be very difficult or impossible. Documented record of human longevity for the last 100 years (with a conservative estimate of data from 8 billion individuals) shows that the limit of human lifespan is around 122 years; the fact that no individual has lived beyond this limit is a clue to the validity of the Zugzwang hypothesis.

Treating Sleep Apnea Lowers Dementia Risk By 20-30%

The results of this epidemiological study suggest that suffering from untreated sleep apnea can raise the risk of later dementia and mild cognitive impairment by 20-30%. How the repeated hypoxia in the brain produced by sleep apnea results in a raised risk of dementia isn't understood in detail, but it has been shown to lead to structural changes in brain regions connected to memory. It is also possible that the correlation of obesity with sleep apnea muddies the waters, and that sleep apnea isn't actually the primary issue, given the harms dcaused by excess visceral fat tissue. That makes the data here interesting, in that it compares treated and untreated patients exhibiting sleep apnea, and finds a meaningful difference.

To examine associations between positive airway pressure (PAP) therapy, adherence, and incident diagnoses of Alzheimer's disease (AD), mild cognitive impairment (MCI), and dementia not-otherwise-specified (DNOS) in older adults, this retrospective study utilized Medicare data of 53,321 beneficiaries, aged 65+, with an obstructive sleep apnea (OSA) diagnosis prior to 2011.

Study participants were evaluated using ICD-9 codes for neurocognitive syndromes [AD(n=1,057), DNOS(n=378), and MCI(n=443)] that were newly-identified between 2011-2013. PAP treatment was defined as presence of ≥1 durable medical equipment (HCPCS) code for PAP supplies. PAP adherence was defined as ≥2 HCPCS codes for PAP equipment, separated by ≥1 month. Logistic regression models, adjusted for demographic and health characteristics, were used to estimate associations between PAP treatment or adherence and new AD, DNOS, and MCI diagnoses.

In this sample of Medicare beneficiaries with OSA, the majority (78%) of beneficiaries with OSA were prescribed PAP (treated), and 74% showed evidence of adherent PAP use. In adjusted models, PAP treatment was associated with lower odds of incident diagnoses of AD and DNOS (odds ratio 0.78). Lower odds of MCI, approaching statistical significance, were also observed among PAP users (odds ratio 0.82). PAP adherence was associated with lower odds of incident diagnoses of AD (odds ratio 0.65). In conclusion, airway pressure treatment and adherence are independently associated with lower odds of incident AD diagnoses in older adults. Results suggest that treatment of OSA may reduce risk of subsequent dementia.


Lysosomal Dysfunction and the Death of Neurons via Ferroptosis

Here find supporting evidence for the SENS view of lipofuscin and lysosomal dysfunction in aging. Lysosomes are the recycling units of the cell, packed with enzymes to break down unwanted structures and molecules into raw materials. Over time, long-lived cells such as the neurons of the central nervous system are negatively affected by the build up of resilient metabolic waste that is challenging to break down. Collectively this waste is called lipofuscin, but it contains many different problem compounds, and overall is poorly catalogued. Lysosomes in old neurons are observed to be bloated and dysfunctional, leading to cells that become overtaken with broken machinery that cannot be recycled. As noted here, the end result is cell death, and an accelerated pace of neural cell death is the road to neurodegenerative conditions.

A toxic brew of lysosomal lipids, reactive iron atoms, and oxidative stress can spell doom for human neurons. This is the upshot of the first-ever CRISPR screens at the genome-wide level in these cells. Researchers used the genome-editing tool to dial up or down expression of each protein-coding gene in the human neuronal genome. They uncovered a surprising connection between endolysosomal processing and the iron-dependent cell-death pathway called ferroptosis.

Zeroing in on that pathway, the researchers found that in the absence of the lysosomal protein prosaposin (PSAP), glycosphingolipids accumulate in the lysosomes, setting off oxidative stress. This results in a toxic mesh of ferrous ions and peroxidized lipids that can kill neurons via the ferroptosis pathway. The findings connect pathways that have been implicated separately in neurodegenerative disease, and support the idea that iron-rich "aging pigments" of lipofuscin, commonly spotted in older brains, might not be so benign after all.

What is the connection between PSAP and ferroptosis? Examining PSAP knockout neurons, the researchers found that the lysosomes were dramatically enlarged, and chock-full of glycosphingolipids. Strikingly, they found that these lipid-logged organelles were also electron-dense, suggesting they were loaded with iron. In fact, these densities bore an uncanny resemblance to lipid-iron granules called lipofuscin, also known as aging pigment. Lipofuscin soaks up the metal ions from the detritus of iron-rich organelles such as mitochondria, and this iron is thought to provoke the production of reactive oxygen species via the Fenton reaction.

Could this cascade play out in the aging brain? All of the culprits are there. For one, oxidative stress is known to rise in the brain with age, and lysosomal function also flags. Levels of not only lipofuscin, but also reactive iron increase in aging brains and even more so in neurodegenerative disease.


A Gene Therapy Platform Applied to Skin Rejuvenation

MRBL is one of the many projects relevant to the treatment of aging that is in George Church's orbit. This is a collection of gene therapy technologies intended for delivery of vectors to areas of skin directly, coupled with analysis of age-related and disease-related gene expression changes in skin cell populations to provide targets. It is a viewed as a basis for approaches in cell reprogramming that could make aged skin cells behave in a more youthful fashion, overriding their response to the age-damaged local environment.

In terms of mechanisms known to be of interest in aging, upregulation of collagen production is an obvious goal, generally agreed upon to be beneficial if achieved. A more interesting but more challenging result to aim for would be the deposition of elastin in a structurally correct manner. Beyond these two, there are many other more subtle issues in cell misbehavior related to the aging of skin, from stem cell activity to coordination of wound healing in the dermis and epidermis.

That said, it isn't clear that forcing more a youthful behavior in cells via gene therapies is the best way forward in all matters relating to aging. It neglects root causes in favor of trying to override them selectively, allowing those root causes to continue to produce all of their other consequences. Chronic inflammation, for example, has a broadly negative impact on tissue function in skin, as is also the case in other organs. Clearing senescent cells, and removing other causes of systemic inflammation, are likely better approaches than trying to force cells to perform correctly, one gene at a time, in an inflamed environment.

MRBL: Next-Generation Gene Therapy for Molecular Skin Rejuvenation

The skin is the largest organ in the body, and carries out multiple vital functions, including protective barrier functions against the loss of moisture and mechanical, UV, and other injuries, immune defense functions, as well as sensory functions. For maintaining its integrity and multifaceted performances, skin relies on a range of different cell types that compose and support its layered organization, each expressing specific molecules that together facilitate physical cell interactions and communication between them, as well as specialized functions.

The gradual decline in the production of many of those molecules is associated with the natural aging process of skin. Separately, a plethora of skin diseases are driven by mutations in single genes that can strike much earlier in life. In both cases, targeted therapeutics that could slow skin aging and directly interfere with the disease pathology of monogenic skin diseases are not available. Commonly applied treatments are merely palliative, reducing the severity symptoms or simply masking the visible damage caused to the skin without actually addressing the condition.

To overcome the lack of truly curative and targeted treatments, a multidisciplinary team has developed a comprehensive gene therapy platform that combines a new computational target discovery platform with improved skin cell-specific adenovirus-associated virus (AAV) gene delivery vehicles, and a novel biomaterials-mediated local delivery of the genetic payloads to affected areas of the skin. Strategically targeting both disease (short-term) and aging (long-term), this next generation skin gene therapy platform builds on the insight that the pathology of genetic diseases often recapitulates specific age-related degenerations.

Fortuitously, researchers found that key targets in aging biology could be leveraged as therapeutics for monogenic diseases, as the genes affected in such diseases were also powerful determinants of the aging process. Using their new-found understanding of aging dynamics, the team has built a time-resolved genetic network of skin aging, and is currently validating novel age-driving genetic targets identified from the resulting map in cell and animal studies.

Denitsa Milanova on MRBL - Gene Therapy for Skin Rejuvenation

I'm working on an Institute Project called MRBL, which essentially enables in situ genetic engineering of the skin. It's a platform technology and has a variety of applications. We started the project looking at the hardest problem - how to solve skin aging at the molecular level. Our gene-potentiating technology could make skin cells go back to their younger state, causing a true rejuvenating effect, and we're trying to get there by modifying the levels of the right fingerprint of genes in the skin.

This technology can also be applied to monogenetic skin diseases, which are diseases that are controlled by the malfunction of a single gene. These conditions manifest in phenotypes like blistering skin and numerous open wounds. With MRBL we are creating novel therapeutics that can correct the levels of such dysfunctional genes or even permanently correct mutations causing injured skin using a skin cell-specific, minimally invasive, adenovirus-associated (AAV)-based gene delivery system.

Beyond that, we are using the same technology to try and leverage the skin as a bioreactor for the production of neutralizing antibodies directly in the body that could help fight HIV, COVID-19 or other infectious diseases. In these instances, the skin is not being treated because it is sick or aging, but instead used as a "factory" to produce therapeutic antibodies or even foreign proteins that stimulate the immune system in a protective way.

Yuva Biosciences as an Example of the Cosmeceuticals Path to Development of Aging Interventions

Yuva Biosciences is attempting to treat skin aging by improving mitochondrial function, and they are taking a cosmeceutical approach. It is far faster and less costly to bring treatments to market via the cosmetics regulatory pathway than via the Investigational New Drug pathway. One has to accept considerable restrictions over what sort of approaches can be used, meaning that one is largely constrained to using combinations of known compounds, taken from a list of those that have been well characterized already. This in turn means that effect sizes tend not to be large.

Historically this has been an industry in which profit is driven by marketing rather than efficacy, so developers have not been all that incentivized to produce products that worked. Targeting the mechanisms of aging will gradually introduce some degree of efficacy into this field, however. Or at least we can hope that this will be the case. We can look at the reduction of cellular senescence in skin following months of topical low dose rapamycin treatment, for example, or the conceptually similar but technically different OneSkin approach to topical senotherapeutics.

With an initial focus on developing cosmeceuticals, US start-up Yuva Biosciences aims to harness mitochondrial science to address skin aging and age-related hair loss. The company has developed a natural topical treatment, imminently about to enter human trials, which it hopes will demonstrate an ability to promote hair growth and reduce skin wrinkles.

During founder Keshav Singh's work to explore whether mice induced with mitochondrial dysfunction were more likely to develop cancer, he came across a surprising result. "The first thing we noticed was that, within four weeks or six weeks, these mice developed skin wrinkles, and lost hair. When we restored the mitochondrial function, the hair grew back. So that gave us a direct link between mitochondrial dysfunction and hair loss and skin aging." The results convinced Singh that he should try to discover a compound that would drive similar results and set about testing a range of natural and pharmaceutical products.

"We derived fibroblast cells from these mice, and did a very targeted screening. And, lo and behold, within a month we found a natural compound that can prevent skin wrinkles and hair loss in mice. So we started Yuva Biosciences and have started work towards commercialising both the initial compound discovered, plus a pipeline of compounds, with a focus on natural compounds, because those can go to market as cosmeceuticals. We're actually starting human trials, and we'll be conducting three trials over the next couple months - two for skin, one for hair. And so that'll provide a lot of exciting results and hopefully some exciting products."


COVID-19 Data Shows the Importance of Thymic Atrophy in Aging

The decline of the immune system is of great importance in aging. Vulnerability to infection, a decreased surveillance of senescent cells and cancerous cells, and growing chronic inflammation all take their toll. A sizable fraction of this problem stems from the diminished supply of new T cells of the adaptive immune system. T cells begin life as thymocytes in the bone marrow, then migrate to the thymus where they mature. Unfortunately, the thymus atrophies with age, a process known as thymic involution, in which active tissue is replaced by fat. The T cell supply falters, and as a result the existing T cell population becomes ever more damaged and dysfunctional. Researchers have shown that raised cancer risk over time maps very well to the pace of thymic involution, and here more data is deployed to point out the same correlation for vulnerability to infectious disease.

Here we report that COVID-19 hospitalisation rates follow an exponential relationship with age, increasing by 4.5% per year of life. This mirrors the exponential decline of thymus volume and T-cell production (decreasing by 4.5% per year). COVID-19 can therefore be added to the list of other diseases with this property, including those caused by MRSA, West Nile virus, Streptococcus Pneumonia, and certain cancers, such as chronic myeloid leukemia and brain cancers. In addition, incidence of severe disease and mortality due to COVID-19 are both higher in men, consistent with the degree to which thymic involution (and the decrease in T-cell production with age) is more severe in men compared to women. For under 20s, COVID-19 incidence is remarkably low.

A Bayesian analysis of daily hospitalisations, accounting for contact-based and environmental transmission, indicates that non-adults are the only age group to deviate significantly from the exponential relationship. Our model fitting suggests under 20s have 53-77% additional immune protection beyond that predicted by strong thymus function alone. We found no evidence for differences between age groups in susceptibility to overall infection, or, relative infectiousness to others. The simple inverse relationship between risk and thymus size we report here suggests that therapies based on T-cell mechanisms may be a promising target.


Nicotinamide Riboside Supplementation Beginning in Mid-Life Slows Osteoporosis in Mice

In today's open access paper, researchers report that long-term supplementation with nicotinamide riboside in mice, starting from mid-life and continuing into old age, slows the pace of osteoporosis. The extracellular matrix of bone tissue is constantly remodeled over time, broken down by osteoclasts and built up by osteoblasts. Osteoporosis is caused by a growing imbalance between these two processes that favors destruction over creation. Bones lose mass and become brittle as a result, eventually becoming a serious health issue.

Many mechanisms are proposed to contribute to osteoporosis. Chronic inflammation, for example, alters the behavior of bone cells in ways that favor the activity of osteoclasts. Senescent cells accumulate with age and the source of a great deal of inflammatory signaling. Selectively destroying senescent cells via senolytic treatments has been shown to reverse osteoporosis to some degree. Another related mechanism involves the formation of advanced glycation endproducts (AGEs) that cross-link matrix proteins. This also is thought to be related to the chronic inflammation of aging.

Of relevance to today's research materials, mitochondrial dysfunction is also implicated in the development of osteoporosis, via its effects on cell development and activities. Mitochondria are the power plants of the cell, and when the supply of chemical energy store molecules created by mitochondria is diminished, near all cell processes suffer in some way.

In recent years, loss of NAD+ has been identified as one of the proximate causes of this issue, this being an important component in the chemical engines that operate inside mitochondria. NAD+ levels fall with age, for reasons that are far from fully explored. Various approaches to NAD+ upregulation have been assessed in mice and human trials, mostly supplementation with compounds derived from vitamin B3 such as nicotinamide riboside. The results in humans have overall been mixed at best. Nonetheless, results such as this one continue to accumulate in mice.

A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging

Here we show that NAD+ supplementation by the NAD+ precursor nicotinamide riboside (NR) can restore a youthful number of osteoprogenitor cells and attenuate skeletal aging in female mice. These, along with the findings that the levels of NAD+ decline with age in osteoblast progenitors, strongly suggest that NAD+ is a major target of aging in osteoblastic cells. A decrease in NAD+ was also seen in bone marrow stromal cells from 15-month-old when compared to 1-month-old mice. In agreement with our findings, long-term administration of NMN increased bone mineral density in male C57BL/6 mice. In contrast, administration of NMN to 12-month-old mice for only 3 months was not sufficient to alter bone mass.

We also found that the protein levels of Nampt in osteoblastic cells from old mice were lower than in cells from young mice. These along with the findings that deletion of Nampt in mesenchymal lineage cells is sufficient to decrease bone mass support the premise that the age-associated decrease in NAD+ in osteoblast progenitors attenuates bone formation. Further support is provided by evidence that NR administration increases osteoprogenitor number and mineralizing surface in aging mice. In tissues such as muscle and intestine, progenitor cells are critical targets of the anti-aging effects of NR. Nonetheless, the systemic nature of NR treatment precludes definitive conclusion about the target cells responsible for the beneficial effects on the skeleton.

We and others have shown that osteoprogenitors from old humans or mice exhibit markers of cellular senescence. Elimination of senescent cells via genetic or pharmacologic manipulations increases bone mass in aged mice, suggesting that cellular senescence contributes to skeletal aging46. Our present findings that NR administration decreases markers of senescence in osteoblast progenitors from old mice provide strong support for the contention that a decline in NAD+ is a major contributor to the age-associated bone cell senescence. This contention is further supported by evidence that a decrease in NAD+ exacerbates replicative senescence in bone marrow-derived stromal cell cultures. NR administration also attenuates cellular senescence in brain and skin of aged mice. Interestingly, in macrophages and endothelial cells Cd38 expression can be induced by factors associated with the senescence-associated secretory phenotype (SASP), suggesting that cellular senescence re-enforces the decline in NAD+.

Based on the results of the present work, we propose that intrinsic defects in osteoblast progenitors that cause a decrease in NAD+ contribute to the age-related decline in bone formation and bone mass. Repletion of NAD+ with precursors such as NR, therefore, may represent a therapeutic approach to age-associated osteoporosis as it does for other age-related pathologies.

Noting the Work of Jim Mellon to Advance the Longevity Industry and Related Research

In the past few years Jim Mellon, high net worth investor and philanthropist, has put in a great deal of time and effort to help push forward the development of a biotech industry focused on intervention in human aging. He has donated to non-profits in the aging research space, set up aging-focused conference series, founded and raised funding for a sizable biotech company in the space, invested in other biotech startups personally, and in general has been very personable and helpful to his fellow travelers and advocates. Would that there were more people with the resources and will to dive into advancing the state of the field in this way.

How does an idea that is too unconventional for mainstream channels get funded? Today, the concept of longevity research is rapidly gaining adoption, but it wasn't long ago that angel investors and the rare NIH grant were the only options for people fighting for increased longevity. Longevity enthusiasts are likely to know names like Peter Thiel, Dmitry Itskov, J. Craig Venter, Sergey Brin, Larry Ellison, and Jeff Bezos for their personal contributions, both as philanthropists and investors. Among angel investors, Jim Mellon was one of the earliest adopters of longevity research. While his fortune has come from various other sectors, he founded Mann Bioinvest, published Cracking the Code, and started praising the healthy longevity strategy back in 2012. With all the progress and setbacks of the last decade, Jim remains optimistic about the field, recently claiming that the world is on the brink of three major revolutions, with increased longevity being one of them.

In biotech, Jim Mellon is most well-known for his role in Juvenescence, which is both a book he authored on biotech investment and a longevity company he co-founded. Juvenescence has its hand in tissue regeneration and cell therapy approaches to healthy longevity via AgeX Therapeutics and LyGenesis. While still at the preclinical stage, LyGenesis has been perhaps the most successful tissue engineering and regenerative medicine company thus far. Separately from Juvenescence, Jim Mellon also played a role as chairman of Regent Pacific during its acquisition of AI firm Deep Longevity last year. He's also invested in Repair Biotechnologies and various other companies outside the scope of Juvenescence.

Beyond his investments, Jim Mellon has also made various donations to longevity nonprofits in recent years, including the UCL Institute of Healthy Ageing, Methuselah Foundation, and SENS Research Foundation, among others. In 2020, he donated £1 million to Oriel College in order to support and advance the study of Longevity Science at Oxford University, the largest donation of its kind.

For better or worse, high-net-worth individuals are imperative to the translation of treatments from the bench to bedside. While some media organizations make negative comments that billionaires are simply attempting to buy their own immortality without regard for anyone else's health, these concerns are largely overblown. Overall, few people have done as much to increase human longevity as Jim Mellon. Beyond putting up his own capital, he's also played a major role in convincing others to do the same, thereby accelerating longevity research and moving us towards a healthier future.


In Horses, the Gut Microbiome Interacts with Mitochondria to Improve Function

The study here is carried out in horses, but it is reasonable to expect to find very similar mechanisms in other mammals. The beneficial populations of the gut microbiome provide metabolites that steer cell function and exist in symbiosis with the host animal. Mitochondria, the power plants of the cell, are the evolved descendants of ancient symbiotic microbes, now an integral part of cellular processes. It is reasonable to think that the one can influence the other directly via signaling processes, as researchers discuss in these materials and elsewhere. In humans, for example, researchers have found that propionate generated by some populations of gut microbes can enhance athletic performance. There are no doubt other signals and metabolites at work as well, yet to be cataloged.

Mitochondria, which can be briefly described as the energy provider of cells, have been shown in recent studies to be interdependent with gut bacteria. In fact, many diseases associated with mitochondrial dysfunction in humans, such as Parkinson's and Crohn's have been linked to changes in the gut microbiome in many previous studies.

"Studying horses is a good way to assess the link between gut bacteria and mitochondria, because the level of exercise, and thereby mitochondrial function, performed by a horse during an endurance race is similar to that of a human marathon runner. For this study we took blood samples from 20 healthy horses of similar age and performance level, at the start and end of the International Endurance Competition of Fontainebleau, an 8-hour horse race in France. These samples provided information about the chemical signals and expression of specific genes, which is the process by which DNA is converted into instructions for making proteins or other molecules. To understand the composition of the horse's gut bacteria metabolites, we obtained fecal samples at the start of the race."

The researchers found that certain bacteria in the gut were linked to the expression of genes by the mitochondria in the cells. Furthermore, the genes that were expressed, or "turned on", were linked to activities in the cell that helped it to adapt to energetic metabolism.

"Interestingly, mitochondria have a bacterial origin - it is thought they formed a symbiotic relationship with other components to form the first cell. This may explain why mitochondria have this line of communication with gut bacteria. Improving our understanding of the intercommunication between the horse and the gut microbiome could help enhance their individual performance, as well as the method by which they are trained and dietary composition intake. Manipulating the gut microbiota with probiotic supplements as well as prebiotics, to feed the good bacteria, could be a way for increasing the health and balance of the microbiome and horses, to better sustain endurance exercise."