Fight Aging! Newsletter, May 9th 2022
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- Compression of Morbidity Not Observed in Nematode Longevity Mutants
- Endothelial Cell Senescence in Pulmonary Fibrosis
- How Much of Late Life Cancer is Easily Avoidable?
- Senolytic and Reprogramming Therapies are Synergistic in Aging Flies
- Is Reversing Paracrine Senescence a Useful Approach to Alleviating the Age-Related Burden of Senescent Cells?
- Natural Killer Cells Oppose In Vivo Reprogramming
- Towards Targeted Gene Therapy for Hair Cell Regeneration in the Inner Ear
- A Trial of NMN Supplementation in Older People
- DNA Double Strand Breaks in the Context of Tauopathy
- Transplantation of Young Bone Marrow into Old Mice Fails to Extend Life Span
- More on GPNMB as a Target for Senolytic Therapies to Clear Senescent Cells
- Partial Reprogramming Improves Liver Regeneration in Mice
- Interactions Between the Aging of the Gut Microbiome and Brain in the Context of Stroke Risk
- Profiling Michael Greve's Fund, Kizoo Technology Ventures
- Towards a Rough Definition for the Optimal Human Diet
Compression of Morbidity Not Observed in Nematode Longevity Mutants
Compression of morbidity is a reduction in the length of time spent in significant illness or disability at the end of life. It is often touted as a goal in human medicine by those who, for various reasons, don't want to talk about the prospects for extending overall life span through progress in medicine. If we think about aging in terms of damage to a machine, then in the simple model of a single form of damage, compression of morbidity would not be expected to occur in response to a slowed accumulation of damage. Fully functional life span would extend, but so would the period of progressive onset of dysfunction.
Humans are machines, albeit very complicated machines. There is some debate over whether compression of morbidity in humans is possible to achieve, or happening at present as a result of improvements in public health and medical technology, in the context of overall life expectancy slowly increasing year over year. This is one of many areas of epidemiology in which data can be assembled to support almost any view of the situation, while definitions and what is actually being measured make a big difference, particularly the specifics of what is meant by "morbidity" in late life.
The roots of aging consist of a number of different forms of molecular damage. They do interact with one another, and tend to make one another worse, accumulating more rapidly as damage grows, but is possible to envisage a situation in which some forms of damage (a) are less influenced than others by public health measures or medical technology, and (b) only produce very significant mortality very late in life. This may or may not in fact be the case, but the accumulation of transthyretin amyloid in the cardiovascular system with age is a possible candidate. It does appear to influence mortality in younger old age, but there is evidence for it to be the majority cause of death in supercentenarians. In this scenario, therapies to treat aging that failed to change the burden of transthyretin amyloid would tend to produce compression of morbidity.
In today's open access paper, researchers note an absence of compression of morbidity in nematode worms subject to longevity-inducing mutations. This change in metabolism lengthens the period of healthy life span but also lengthens the period of disability in proportion - which is akin to the simple model of a damaged mechanism mentioned above. This work is also an example of the importance of details when it comes to the assessment of morbidity; the paper is in a part a discussion of a novel means for determining whether an old nematode is in fact decrepit, with the implication that earlier studies were not assessing degeneration well enough or in a relevant way.
Longevity interventions temporally scale healthspan in Caenorhabditis elegans
The continuously growing elderly population is projected to result in 1.5 billion people older than 65 years globally by 2050. This poses a significant challenge, as old age is the major risk factor for developing cancer, dementia, cardiovascular, and metabolic diseases, especially because people suffer for approximately 20% of their lifespan from one or multiple of these chronic illnesses, which are themselves accompanied by other late-life disabilities. Current estimates indicate that delaying the onset of these chronic diseases by one year would save 38 trillion in the US alone. Therefore, major research efforts are dedicated to understanding how to increase the time spent in good health (i.e., healthspan) and to postpone and compress the time spent suffering from age-related pathologies and chronic diseases (i.e., sickspan).
Mutations in genes that promote longevity in model organisms, such as Caenorhabditis elegans, have been instrumental in identifying mechanisms that promote healthy aging. A recent study has questioned this approach of using C. elegans longevity mutants to gain insights for promoting healthy aging or mechanisms that prolong healthspan. Using four matrices (resilience to heat and oxidative stress, voluntary movement, and swimming performance) to assess the "health" status of aging C. elegans, they found that four commonly used longevity mutants outperformed wild type at any given time point at older ages, consistent with previous reports. However, compared with their maximum lifespan, longevity mutants displayed an increased sickspan-to-healthspan ratio compared with wild type. Other studies have not observed an increase of sickspan in long-lived C. elegans mutants, except in the case of lower mobility or movement scores for the insulin/IGF-1 receptor longevity daf-2 mutants.
Although all these studies showed that sickspan is not increased in longevity mutants, the question remained about how healthspan changes when the lifespan is extended. We hypothesized that using other health matrices independent of voluntary or behavioral influences, such as physical properties of muscular strength, which is one of the best predictors for all-cause mortality in humans, we might be able to quantify the health trajectory of C. elegans longevity mutants.
Here we confirm that voluntary movement during aging declines, and this fragility is not extended in longevity mutants, except mildly in daf-2 mutants, using high-resolution lifespan and movement measurements on plates. We developed a novel microfluidic device and applied acoustophoretic force fields to quantify the maximum force and power of C. elegans. Using a high-frequency and high-power acoustic force field, it becomes possible to set up a contactless, constant in time, and uniform force field acting along the whole C. elegans body. Therefore, this force field challenges swimming C. elegans in a similar way body-weight exercises do for humans in a gravity field. Furthermore, applying the acoustic field stimulated a swimming response of resting C. elegans. All longevity mutants showed delayed onset of the decline in maximum force and dynamic power during aging. We observed heterogeneity between individuals across all genotypes in the onset of age-related phenotypes, several correlated phenotypes, and a time-dependent occurrence of multiple disabilities. However, we did not find a compression of sickspan but rather a temporal scaling of healthspan relative to their maximal lifespan across genotypes.
Endothelial Cell Senescence in Pulmonary Fibrosis
Cellular senescence is now well recognized as an important contributing cause of fibrosis, a malfunction of normal tissue maintenance that involves deposition of excess collagen into scar-like structures that degrade tissue function. Pulmonary fibrosis is one of the better studied age-related fibrotic conditions, and over the past decade it has been increasingly linked to cellular senescence. Some of the first clinical trials of senolytic drugs to clear senescent cells, using the dasatinib and quercetin combination, were carried out in patients with idiopathic pulmonary fibrosis.
Senescent cells cause harms, such as the disruption of regenerative processes that leads to fibrosis, via the signals that they generate, the pro-inflammatory, pro-growth senescence-associated secretory phenotype (SASP). How exactly does the SASP produce fibrosis, however? Today's open access paper is an example of the research initiatives presently attempting to answer that question. The focus here is on the production of excess fibroblasts, cells that produce the collagen structures of the extracellular matrix, in the context of fibrosis, and the mechanisms by which this happens.
Endothelial Cell Senescence Exacerbates Pulmonary Fibrosis Potentially Through Accelerated Endothelial to Mesenchymal Transition (PDF)
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by progressive lung fibrosis and obliteration of normal alveolar structures. Myofibroblasts play a central role in the progression of IPF by producing excess amount of extracellular matrix, and these myofibroblasts show heterogenous origins including resident fibroblasts, epithelial cells via epithelial to mesenchymal transition (EMT) and endothelial cell (EC) via endothelial to mesenchymal transition (EndMT).
Although lung aging has been considered as essential mechanisms through abnormal activation of epithelial cells and fibroblasts, little is known about a role of EC senescence in the pathogenesis of IPF. Here, we reveal a detrimental role of EC senescence in IPF by utilizing unique EC-specific progeroid mice. EC-specific progeroid mice showed deteriorated pulmonary fibrosis in association with an accelerated EndMT in the lungs after intratracheal bleomycin instillation. We further confirmed that premature senescent ECs were susceptible to EndMT in vitro. Because senescent cells affect nearby cells through senescence-associated secretory phenotype (SASP), we assessed a potential role of the EC-SASP in EMT and myofibroblastic transition of resident fibroblasts. EC-SASP enhanced the myofibroblastic transition in resident fibroblasts, while no effect was detected on EMT.
Our data revealed a previously unknown role of EC senescence in the progression of IPF, and thus rejuvenating ECs and/or inhibiting EC-SASP is an attracting therapeutic strategy for the treatment of IPF.
How Much of Late Life Cancer is Easily Avoidable?
A range of data on the benefits produced by simple health interventions in late life suggests that many people are self-sabotaging to a point at which a significant fraction of age-related disease and mortality might be legitimately thought of as being self-inflicted. To pick one example, if programs of moderate exercise improve health and reduce mortality in old people, which they do, then the conclusion must be that older people are harming themselves by not undertaking sufficient exercise.
Cancer is one of the more important classes of age-related condition. It is age-related for a range of reasons, such as rising levels of chronic inflammation that make the tissue environment more hospitable to cancerous growth, and the progressive failure of the immune system to identify and destroy pre-cancerous and cancerous cells at the earliest stages. If people adopt better lifestyle choices or other simple interventions that reduce these and other issues, then how much of cancer might be avoided? Today's open access paper reports on study results suggesting the answer to that question is perhaps a larger fraction than one might have thought.
A combination of three simple treatments may reduce invasive cancer risk by 61% among adults aged 70+
Mechanistic studies have shown that vitamin D inhibits the growth of cancer cells. Similarly, omega-3 may inhibit the transformation of normal cells into cancer cells, and exercise has been shown to improve immune function and decrease inflammation, which may help in the prevention of cancer. However, there was a lack of robust clinical studies proving the effectiveness of these three simple interventions, alone or combined.
Researchers conducted the DO-HEALTH trial: a three-year trial in five European countries (Switzerland, France, Germany, Austria, and Portugal) with 2,157 participants. The results show that all three treatments, vitamin D3, omega-3s, and simple home strength exercise program (SHEP), had cumulative benefits on the risk of invasive cancers. Each of the treatments had a small individual benefit but when all three treatments were combined, the benefits became statistically significant, and the researchers saw an overall reduction in cancer risk by 61%.
Combined Vitamin D, Omega-3 Fatty Acids, and a Simple Home Exercise Program May Reduce Cancer Risk Among Active Adults Aged 70 and Older: A Randomized Clinical Trial
Generally healthy community-dwelling adults ≥70 years were recruited. The intervention was supplemental 2000 IU/day of vitamin D3, and/or 1 g/day of marine omega-3s, and/or a simple home strength exercise (SHEP) programme compared to placebo and control exercise. In total, 2,157 participants (mean age 74.9 years; 61.7% women; 40.7% with 25-OH vitamin D below 20 /ml, 83% at least moderately physically active) were randomized.
Over a median follow-up of 2.99 years, 81 invasive cancer cases were diagnosed and verified. For the three individual treatments, the adjusted hazard ratios (HRs) were 0.76 for vitamin D3, 0.70 for omega-3s, and 0.74 for SHEP. For combinations of two treatments, adjusted HRs were 0.53 for omega-3s plus vitamin D3; 0.56 for vitamin D3 plus SHEP; and 0.52 for omega-3s plus SHEP. For all three treatments combined, the adjusted HR was 0.39.
Senolytic and Reprogramming Therapies are Synergistic in Aging Flies
Today's open access preprint paper touches on the important topic of synergy between therapies targeting mechanisms of aging. For a variety of reasons, far too little work in academia and industry is conducted on combinations of therapies, and not just for the treatment of aging. Intellectual property, bounds of domain knowledge, academic publishing incentives, and organizational inertia make it much harder to commit to the evaluation of two or more different therapies in combination than to focus only on one approach. This has always been the case in medical development, but it is a critical problem in the context of treating age-related disease by targeting the underlying mechanisms of aging. Aging has numerous distinct causes, and age-related diseases are the combined outcome of multiple distinct processes. Only limited benefits can be obtained by focusing on only one of those causes.
The end goal for the treatment of aging as a medical condition must be to address every important mechanism, employing a collection of therapies. In the early stages of the lengthy development process leading to that end goal, evaluation combinations of therapies will be an important part of optimizing ongoing allocation of time and resources. Yet next to no work is conducted on combination studies, and there is little prospect for an expansion of that work on the part of academia and industry, because of the established incentives. This may be a part of the field in which philanthropic ventures will have to do the heavy lifting. See, for example, the proposed later stages of the Astera Institute's Rejuvenome program.
Combining Stem Cell Rejuvenation and Senescence Targeting to Synergistically Extend Lifespan
Stem cells play a pivotal role in this tissue homeostasis by providing a reservoir of pluripotent precursor cells, needed to replace fully differentiated cells that are lost or damaged. At the opposite end of the cell-fate spectrum are senescent cells, or cells that have permanently withdrawn from the cell cycle. By entering permanent replicative arrest, senescent cells prevent mutations from expanding, thereby providing a sink for genotoxic damage. However, the senescent state does not simply result in passive replicative arrest but instead leads to transcriptional changes causing resistance to apoptosis and increased secretion of pro-inflammatory signaling molecules, a process known as Senescence Associated Secretory Phenotype (SASP). Senescent cell induced SASP in turn promotes inflammation and contributes to age-dependent dysfunction and to the development of age-related diseases.
While the number of stem cells decreases in aging animals, senescent cells accumulate with age. Manipulating cell fates by cellular reprogramming (to rejuvenate somatic cells) and by senolytic interventions (to remove senescent cells) are two promising approaches to restore homeostasis in aged individuals and to prevent age-dependent diseases.
Accumulation of senescent cells and loss of stem cells are not independent processes. Through SASP, senescent cells release large amounts of pro-inflammatory cytokines which contribute to chronic inflammation and mTOR activation, ultimately leading to stem cell exhaustion. This interaction suggests that senolytic therapies might interact with cellular reprogramming strategies in delaying age-dependent decline and disease. We have previously explored drug-drug interactions as synergistic aging interventions, and here we ask whether a combinatorial treatment of the Yamanaka factors (OKSM) and senolytic (Sen) expression could mitigate or reverse the effects of aging more efficiently than either intervention alone. To test this hypothesis, we induced expression of OKSM, Sen and an OKSM-Sen combination in adult flies and compared their effects on health and lifespan.
We find that each treatment alone had limited benefits, with OKSM alone benefiting maximum lifespan at the expense of healthspan while Sen expression alone increased mean lifespan but had no effect on maximum lifespan. In contrast, animals subjected to the combined intervention experienced substantially longer mean and maximum lifespan. Our data is consistent with a synergistic interaction between the two interventions, simultaneously rejuvenating stem cells and removing senescent cells.
Is Reversing Paracrine Senescence a Useful Approach to Alleviating the Age-Related Burden of Senescent Cells?
RNA splicing is the step in gene expression at which pieces of a gene are assembled into the final messenger RNA that encodes the resulting protein. A gene consists of intron sequences (omitted) and exon sequences (included). In some cases different combinations are produced normally and result in different proteins arising from the one gene. In other cases, such different combinations are entirely abnormal and should not occur in a healthy cell. With aging, breakages in the splicing process can result in the appearance of these broken proteins, or in changes in the normal balance of several different proteins produced from the same gene.
You might recall that SENISCA was founded to develop therapies based on reducing the age-related dysregulation of splicing that occurs in tissues throughout the body. The principals of that company argue for splicing dysregulation to be included among the hallmarks of aging, with the idea that it can produce much the same sort of disarray in gene expression as results from epigenetic dysregulation. One of the more interesting aspects of this work on correction of splicing is that it can reverse cellular senescence, in vitro. Accumulation of senescent cells is an important aspect of degenerative aging, and there appears to be a fairly deep connection between certain forms of splicing dysregulation and the onset and maintenance of cellular senescence.
Is it a good idea to restore senescent cells, however? Lorna Harris of SENISCA presented on her work at the recent Longevity Leaders World Congress conference, and the first audience question was exactly that. Yes, you can reverse senescence, but senescent cells are senescent for a reason, so is this restoration wise? Isn't it better to take the senolytic approach and destroy all of these errant cells? In answer, Harris explained her position as being that (a) the SENISCA therapeutics are only restoring cell cycle activity in cases of paracrine senescence, cells that are senescent because nearby senescent cells are encouraging them to adopt that state, and (b) the SENISCA therapeutics will not reverse senescence in profoundly damaged cells.
More data is needed to concretely back up that assertion, but it doesn't seem unreasonable. Not all senescent cells are identical in their regulation of the senescent state, and their state depends on cell type and mode of induction of senescence. That is not very controversial, but equally not very well mapped either. Setting aside the sketchy state of knowledge regarding variations between types of senescent cell, one possible reason to avoid reversal of paracrine senescence is the evidence to suggest that the process of becoming senescent produces significant nuclear DNA damage. Thus even undamaged cells may gain potentially problematic mutations when coerced into senescence by the signaling of other senescent cells.
At the end of the day, prospective risks involving cell damage and the prospect of cancer will have to be quantified with at least lengthy animal studies. That will no doubt happen here in the fullness of time, just as it will for many other approaches to treat age-related diseases by targeting hallmarks of aging.
Natural Killer Cells Oppose In Vivo Reprogramming
Research community is interested in the production of therapies to treat aging and age-related conditions based on partial reprogramming, exposing somatic cells to the Yamanaka factors for long enough to produce a rejuvenation of epigenetic patterns, but not long enough to change cell state. Reprogramming comes with an attendant risk of cancer, and reprogramming shares at least some molecular commonalities with the biochemistry of cancer cells, apparently enough so that the immune system will step in. The data presented in this paper supports a role for natural killer cells in destroying cells that are undergoing in vivo reprogramming. Evidently, this isn't enough to prevent benefits from occurring in past animal studies of reprogramming, but it may be a hurdle on the way to producing therapies for human patients.
The ectopic expression of the transcription factors OCT4, SOX2, KLF4, and MYC (Yamanaka factors, OSKM) enables reprogramming of differentiated cells into pluripotent embryonic stem cells. Methods based on partial and reversible in vivo reprogramming are a promising strategy for tissue regeneration and rejuvenation. However, little is known about the barriers that impair reprogramming in an in vivo context.
We report that natural killer (NK) cells significantly limit reprogramming, both in vitro and in vivo. Cells and tissues in the intermediate states of reprogramming upregulate the expression of NK-activating ligands, such as MULT1 and ICAM1. NK cells recognize and kill partially reprogrammed cells in a degranulation-dependent manner. Importantly, in vivo partial reprogramming is strongly reduced by adoptive transfer of NK cells, whereas it is significantly increased by their depletion. Notably, in the absence of NK cells, the pancreatic organoids derived from OSKM-expressing mice are remarkably large, suggesting that ablating NK surveillance favours the acquisition of progenitor-like properties.
We conclude that NK cells pose an important barrier for in vivo reprogramming, and speculate that this concept may apply to other contexts of transient cellular plasticity.
Towards Targeted Gene Therapy for Hair Cell Regeneration in the Inner Ear
Age-related deafness is caused by some mix of loss of sensory hair cells of the inner ear, and loss of connections between those cells and the brain. A range of potential approaches to restore those cells are under development, and the work here is an example of this sort of work. Researchers have constructed an AAV viral vector that has some specificity for hair cells and nearby supporting cells, and which can be used to deliver a gene therapy payload that converts those supporting cells into new hair cells.
Cells of the cochlea, such as hair cells (HCs) and supporting cells (SCs), are essential for hearing. While sensorineural hearing loss can result from genetic mutations in both HCs and SCs, non-genetic stresses, such as noise, ototoxic medicines, or aging, can also induce deafness through damaging HCs. In either case, these damages are irreversible in mammals who do not have the ability to regenerate cochlear cells. Notably, SCs have the potential to transdifferentiate into HC-like cells.
Gene therapies have emerged as important treatments for genetic diseases, and current progress also demonstrates their potential for treating hearing loss. Several genes, such as tmc1, clrn, and otof, when being delivered to cochleae, can restore hearing function in animal models. Adeno-associated viruses (AAVs) have been shown to possess high safety in both animal models and humans. Previously, we developed a synthetic AAV, AAV-ie, which targets SCs and HCs. AAV-ie can regenerate HC-like cells through delivering the transcription factor, Atoh1, which transdifferentiates SCs into HC-like cells. However, its targeting efficiencies for SCs or HCs need to be improved, especially in the basal region of cochleae.
In the present study, we performed mutational screening on the AAV-ie capsid. We generated a repertoire of mutants on the amino acid sequence of AAV-ie capsids to manipulate phosphorylation/ubiquitination of AAVs in cells. We demonstrated that a particular amino acid-mutant AAV-ie capsid, AAV-ie-K558R, can transduce SCs with high efficiency and is suitable for correcting dysfunctional genetic mutations or for HC-like regeneration.
A Trial of NMN Supplementation in Older People
Levels of nicotinamide adenine dinucleotide (NAD) are relevant to mitochondrial function and decline with age for reasons that are only partially explored. Proximate causes are well outlined, the faltering of salvage and synthesis pathways due to lower levels of necessary molecules, but the connections to deeper causes of aging remain to be mapped. When it comes to NAD+ upregulation via vitamin B3 derivatives, boosting the operation of those pathways, there is more human data for nicotinamide riboside (NR) than for nicotinamide mononucleotide (NMN), so it is interesting to see the trial data here. It remains a question as to whether approaches that upregulate NAD are worth pursuing, given that they don't appear be any better than regular exercise programs at raising NAD levels, and the clinical trial data that assessed actual benefits to patients is very mixed.
It has been widely reported that mammalian intracellular NAD levels decrease significantly during aging and the decline has profound impact on aging related health issues. β-Nicotinamide mononucleotide (NMN) supplementation as a precursor to boost intracellular NAD has proven highly effective and safe in many animal studies. However, only limited number of human clinical trials have been done on NMN.
This randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent human clinical trial was done at two clinical centers in Pune, India. 84 healthy middle-aged and older adults (40 - 65 years old) of both males and females were screened. 80 were recruited, randomized, and stratified in 1:1:1:1 ratio for a 60-day clinical study with once daily oral dosing of placebo, 300mg, 600mg, and 900mg NMN which were dispensed and monitored by principal investigators at the clinical centers.
Blood intracellular NAD levels were found statistically significantly increased among all NMN treated groups. The mean percentage increases of blood cellular NAD levels over baselines at day 30 were 21.20%, 151.70%, 390.70%, and 312.82% for placebo, 300mg, 600mg, and 900mg respectively while at day 60, the increases were 45.10%, 175.80%, 470.30%, and 364.31% for placebo, 300mg, 600mg, and 900mg respectively. The similar results were observed with the distances in six-minute walking test for physical endurance assessment. The mean percentage increases of the distance walked in six minutes over baselines were -4.56%, 13.88%, 38.10%, and 31.48% at day 30 and 1.60%, 23.64%, 50.18%, and 48.4% at day 60 for placebo, 300mg, 600mg, and 900mg respectively.
DNA Double Strand Breaks in the Context of Tauopathy
The accumulation of altered tau protein, forming harmful aggregates, is a feature of a number of age-related neurodegenerative conditions, classed as tauopathies. This interesting paper discusses the evidence for tauopathies to be associated with an increased burden of double strand breaks, a form of DNA damage. Such damage is disruptive if prevalent, and recent evidence suggests that even repaired double strand breaks alter cell epigenetics in ways that encourage age-related declines in cell function. The researchers here suggest a bidirectional relationship, with tau pathology both degrading DNA repair mechanisms, and being driven by DNA damage.
DNA double-strand break (DSB) is the most severe form of DNA damage and accumulates with age, in which cytoskeletal proteins are polymerized to repair DSB in dividing cells. Since tau is a microtubule-associated protein, we investigate whether DSB is involved in tau pathologies in Alzheimer's disease (AD). First, immunohistochemistry reveals the frequent coexistence of DSB and phosphorylated tau (p-tau) in the cortex of AD patients. In vitro studies using primary mouse cortical neurons show that non-p-tau accumulates perinuclearly together with the tubulin after DSB induction with etoposide, followed by the accumulation of phosphorylated tau. Moreover, the knockdown of endogenous tau exacerbates DSB in neurons, suggesting the protective role of tau on DNA repair.
Interestingly, synergistic exposure of neurons to microtubule disassembly and the DSB strikingly augments aberrant p-tau aggregation and apoptosis. These data suggest that DSB plays a pivotal role in AD-tau pathology and that the failure of DSB repair leads to tauopathy.
In summary, neurons are physiologically exposed to various crises, such as aging, oxidative stress, genetic mutation, and excitotoxicity, all of which cause DNA damage. Under normal conditions, when DNA damage occurs, cytoskeletal proteins, such as microtubules, polymerize to execute DNA repair, and they might form a link with the nuclear membrane for the repair. Tau may well be involved in the rearrangement of microtubules to assist this process. However, the excessive DNA damage may cause accumulation of p-tau and may disassemble microtubules, which may exacerbate DNA damage and lead to neuronal cell death.
Transplantation of Young Bone Marrow into Old Mice Fails to Extend Life Span
Researchers here report on a study of transplantation of bone marrow from young mice to old mice, showing that it improves some measures of immune function, but fails to extend life span. One can compare this with a study from a few years back in which the same approach did in fact extend remaining life span in the old mice. Failures of this nature, where one would expect there to be benefits, are a challenge, as it remains the case that we expect benefits to result if the process was only better optimized in some way. It is hard to draw the line and say that a particular implementation will not work, and why it will not work, without a great deal of further work.
The stem cell theory of aging postulates that stem cells become inefficient at maintaining the original functions of the tissues. We, therefore, hypothesized that transplanting young bone marrow (BM) to old recipients would lead to rejuvenating effects on immunity, followed by improved general health, decreased frailty, and possibly life span extension. We developed a murine model of non-myeloablative heterochronic BM transplantation in which old female BALB/c mice at 14, 16, and 18(19) months of age received altogether 125.1 ± 15.6 million nucleated BM cells from young male donors aged 7-13 weeks. At 21 months, donor chimerism was determined, and the immune system's innate and adaptive arms were analyzed. Mice were then observed for general health and frailty until spontaneous death, when their lifespan, post-mortem examinations, and histopathological changes were recorded.
The results showed that the old mice developed on average 18.7 ± 9.6% donor chimerism in the BM and showed certain improvements in their innate and adaptive arms of the immune system, such as favorable counts of neutrophils in the spleen and BM, central memory Th cells, effector/effector memory Th and Tc cells in the spleen, and B1a and B1b cells in the peritoneal cavity. Borderline enhanced lymphocyte proliferation capacity was also seen. The frailty parameters, pathomorphological results, and life spans did not differ significantly in the transplanted vs. control group of mice. In conclusion, although several favorable effects are obtained in our heterochronic non-myeloablative transplantation model, additional optimization is needed for better rejuvenation effects.
More on GPNMB as a Target for Senolytic Therapies to Clear Senescent Cells
You might recall that researchers recently demonstrated that vaccination against GPNMB is a senolytic strategy, reducing the harmful burden of senescent cells in aged tissues by directing the immune system to destroy these cells. Here the same team reports on their further investigation of the role of GPNMB in senescent cells. Why is GPNMB expression upregulated in senescent cells to the point of it being a good target for immune based senolytic therapies? The answer appears to be that it is protective against certain forms of stress inherent in the state of cellular senescence.
Accumulation of senescent cells in various tissues has been reported to have a pathological role in age-associated diseases. Elimination of senescent cells (senolysis) was recently reported to reversibly improve pathological aging phenotypes without increasing rates of cancer. We previously identified glycoprotein nonmetastatic melanoma protein B (GPNMB) as a seno-antigen specifically expressed by senescent human vascular endothelial cells and demonstrated that vaccination against Gpnmb eliminated Gpnmb-positive senescent cells, leading to an improvement of age-associated pathologies in mice.
The aim of this study was to elucidate whether GPNMB plays a role in senescent cells. We examined the potential role of GPNMB in senescent cells by testing the effects of GPNMB depletion and overexpression in vitro and in vivo. Depletion of GPNMB from human vascular endothelial cells shortened their replicative lifespan and increased the expression of negative cell cycle regulators. Conversely, GPNMB overexpression protected these cells against stress-induced premature senescence. Depletion of Gpnmb led to impairment of vascular function and enhanced atherogenesis in mice, whereas overexpression attenuated dietary vascular dysfunction and atherogenesis.
In conclusion, our results taken together with the above considerations demonstrated that GPNMB was upregulated by lysosomal stress associated with cellular senescence and acted as a protective factor for senescent cells, and suggest that targeting cell/tissue-specific seno-antigens like GPNMB could be a reasonable strategy for next-generation senolytic therapy with higher selectivity and fewer off-target effects.
Partial Reprogramming Improves Liver Regeneration in Mice
While much of the focus on cell reprogramming these days is upon the ability of reprogramming factors to produce epigenetic and functional rejuvenation, there are other lines of research. Here, researchers show that short-term exposure to reprogramming factors can improve liver regeneration in mice. This is interesting, but as noted the liver is a very regenerative organ in comparison to other mammalian tissues, and the mechanisms of regeneration may be distinct from other tissues. Thus the ability to improve regeneration in the liver via reprogramming may or may not generalize to other organs.
Researchers previously showed how four cellular reprogramming molecules Oct-3/4, Sox2, Klf4, and c-Myc, also called "Yamanaka factors", can slow down the aging process as well as improve muscle tissue regeneration capacity in mice. In their latest study, the authors used Yamanaka factors to see if they could increase liver size and improve liver function while extending the health span of the mice. The process involves partially converting mature liver cells back to "younger" states, which promotes cell growth.
The issue many researchers in the field face is how to control the expression of factors needed for improving cell function and rejuvenation as some of these molecules can cause rampant cell growth, such as occurs in cancer. To circumvent this, researchers used a short-term Yamanaka factor protocol, where the mice had their treatment administered for only one day. The team then tracked the activity of the partially reprogrammed liver cells by taking periodic samples and closely monitoring how cells divided over several generations. Even after nine months - roughly a third of the animal's life span - none of the mice had tumors.
"Yamanaka factors are truly a double-edged sword. On the one hand, they have the potential to enhance liver regeneration in damaged tissue, but the downside is that they can cause tumors. We were excited to find that our short-term induction protocol has the good effects without the bad-improved regeneration and no cancer."
Interactions Between the Aging of the Gut Microbiome and Brain in the Context of Stroke Risk
The gut microbiome changes with age in ways that provoke greater chronic inflammation in the body, as well as reducing the production of beneficial metabolites, such as those that influence neurogenesis. When thinking about stroke resulting from the progression of atherosclerosis and hypertension, inflammation is an important factor, but there are other mechanisms that might link the aging of the gut microbiome and the aging of the vasculature in the brain. Some of these connections are discussed in the open access review paper noted here.
The microbiota-gut-brain-axis (MGBA) is a bidirectional communication network between gut microbes and their host. Many environmental and host-related factors affect the gut microbiota. Dysbiosis is defined as compositional and functional alterations of the gut microbiota that contribute to the pathogenesis, progression and treatment responses to disease. Dysbiosis occurs when perturbations of microbiota composition and function exceed the ability of microbiota and its host to restore a symbiotic state. Dysbiosis leads to dysfunctional signaling of the MGBA, which regulates the development and the function of the host's immune, metabolic, and nervous systems.
Dysbiosis-induced dysfunction of the MGBA is seen with aging and stroke, and is linked to the development of common stroke risk factors such as obesity, diabetes, and atherosclerosis. Changes in the gut microbiota are also seen in response to stroke, and may impair recovery after injury. In this review relevant MGBA components are introduced and summarized for a better understanding of age-related changes in MGBA signaling and its dysfunction after stroke. We will then focus on the relationship between the MGBA and aging, highlighting that all components of the MGBA undergo age-related alterations that can be influenced by or even driven by the gut microbiota.
In the final section, the current clinical and preclinical evidence for the role of MGBA signaling in the development of stroke risk factors such as obesity, diabetes, hypertension, and frailty are summarized, as well as microbiota changes with stroke in experimental and clinical populations. We conclude by describing the current understanding of microbiota-based therapies for stroke including the use of prebiotics/probiotics and supplementations with bacterial metabolites. Ongoing progress in this new frontier of biomedical sciences will lead to an improved understanding of the MGBA's impact on human health and disease.
Profiling Michael Greve's Fund, Kizoo Technology Ventures
Philanthropist and investor Michael Greve directs funds into advocacy, research, and commercial development of SENS-like projects aimed at repair of underlying mechanisms of aging. His Forever Healthy Foundation undertakes a range of useful activities, such as reviewing existing therapies that may address aspects of aging, and running the Undoing Aging conference series. His venture fund, Kizoo, has invested in a range of biotech companies developing interventions for aging, most of which are in some way connected to the SENS outline for rejuvenation biotechnology.
Kizoo is investing 300 million in a portfolio of private science-backed biotechnology companies which are working to tackle age-related diseases. The funds underline Kizoo's commitment to these startups with the aim of advancing therapies from clinical development to patient. Startup projects include the decalcification of aged tissue, breaking of protein-glucose cross-links, and the delivery of new mitochondria to aged cells. These aim to prevent and repair age-related conditions such as myocardial infarction, stroke, high blood pressure, tissue stiffening, skin ageing, and loss of muscle function.
It's a grand proposition, but owner Michael Greve is very clear on his pursuit of these goals. "It's a personal thing for me. You can look after your lifestyle but eventually you come to realise you can't diet yourself healthy forever. Sooner or later you'll be susceptible to age-related diseases due to the ageing process. This is how I became interested in this field. Basically, all my entrepreneurial energy shifted to this area - rejuvenation biotech."
Greve acknowledges that globally there has been a significant shift to learn more about age-related diseases (ARDs) and that we have reached the point where we can keep them under medical control. Of course, ARD is a broad clinical area - anything from osteoporosis to some forms of cancer. Greve explains that there are two paradigms that are similar. One is the hallmarks of ageing and the other is the Strategies for Engineered Negligible Senescence (SENS) paradigm, which goes to the root of the issue. Greve and his team are working on the root causes to therefore prevent ARDs entirely.
Kizoo's strategy is to define this as a new sector in drug discovery. In order to drive this field, Kizoo makes what it calls 'lighthouse investments'. "These are part of our investment paradigm and are things that have never been done before but have the potential to become game-changers. We have several points that we want to prove with our investments. When we talk about age-related diseases and rejuvenation, many people think it's science fiction. We want to show this is not the case and that the reality of a pill or an injection to tackle the root cause is possible. We also want to demonstrate that it's going to be inexpensive and that the therapeutics will be for everybody. Finally, we want to make the public understand that what we are trying to do is uncomplicated."
Towards a Rough Definition for the Optimal Human Diet
It seems plausible that there is a roughly optimal human diet, a range within which one will age modestly more slowly than is the case when falling outside it. The work on fasting mimicking is quite solid, for example. What does one eat when not in a period of fasting mimicking, however? On this topic, the science tends to get drowned out by the marketing, ever a human failing. Given a more coordinated scientific community, it could be possible to produce data that is compelling, however, a reasonable and defensible answer to the question. Just don't expect that to turn up any time soon, or for it to settle the diet wars when it does.
Examining a range of nutrition research from studies in laboratory animals to epidemiological research in human populations provides a clearer picture of the best diet for a longer, healthier life. Researchers recently described the "longevity diet," a multi-pillar approach based on studies of various aspects of diet, from food composition and calorie intake to the length and frequency of fasting periods. The researchers reviewed hundreds of studies on nutrition, diseases, and longevity in laboratory animals and humans and combined them with their own studies on nutrients and aging.
The work also included a review of different forms of fasting, including a short-term diet that mimics the body's fasting response, intermittent fasting (frequent and short-term) and periodic fasting (two or more days of fasting or fasting-mimicking diets more than twice a month). In addition to examining lifespan data from epidemiological studies, the team linked these studies to specific dietary factors affecting several longevity-regulating genetic pathways shared by animals and humans that also affect markers for disease risk. These include levels of insulin, C-reactive protein, insulin-like growth factor 1, and cholesterol.
The authors report that the key characteristics of the optimal diet appear to be moderate to high carbohydrate intake from non-refined sources, low but sufficient protein from largely plant-based sources, and enough plant-based fats to provide about 30 percent of energy needs. Ideally, the day's meals would all occur within a window of 11-12 hours, allowing for a daily period of fasting. Additionally, a 5-day cycle of a fasting or fasting-mimicking diet every 3-4 months may also help reduce insulin resistance, blood pressure, and other risk factors for individuals with increased disease risks.
The next step in researching the longevity diet will be a 500-person study taking place in southern Italy. In addition to the general characteristics, the longevity diet should be adapted to individuals based on sex, age, health status, and genetics. For instance, people over age 65 may need to increase protein in order to counter frailty and loss of lean body mass.