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- A Popular Science Article on Young Blood versus Old Blood in the Development of Treatments for Aging
- Aging as an Emergent Phenomenon, All Trees and No Forest
- Clarifying the Hyperfunction Theory of Aging
- On the Benefits of Estrogens in the Context of Longevity Differences by Gender
- Better Mapping Age-Related Changes in the Human Gut Microbiome
- Well Structured Cartilage Grown from Embryonic Stem Cells
- Treadmill Training for Old Mice Upregulates Autophagy and Improves Heart Function
- Radiation Treatment Persistently Alters Heart Cell Function to Produce Benefits in Heart Failure Patients
- How Much of the Benefit of a Healthier Diet is Due to Natural Calorie Restriction Mimetics?
- Icariin Treatment Improves the Aging Gut Microbiome in Mice
- Preprint of the Paper Summarizing the Leucadia Therapeutics Hypothesis and Evidence on the Cause of Alzheimer's Disease
- Longevity Science Foundation Commits to 1 Billion in Research Funding Over the Next Decade
- Age versus Frailty as a Predictor of Mortality
- Senescent Mesenchymal Cells Cause Localized Inflammation in Osteoarthritic Cartilage
- More on NeuroD1 Gene Therapy to Restore Neural Function Following Injury and Scarring
A Popular Science Article on Young Blood versus Old Blood in the Development of Treatments for Aging
The popular science article I'll point out today does a fair job of following the past decade or so of work arising from heterochronic parabiosis, in which the circulatory systems of a young animal and an old animal are joined. The young animal exhibits some degree of accelerated aging, while the old animal exhibits some degree of rejuvenated function. The question all along has been why exactly this happens: what are the underlying mechanisms, and can they be replicated as a basis for therapy.
The obvious first approach was to transfuse young donor blood into old recipients, as positive results would mean that the existing blood transfusion infrastructure could be used to provide a relatively low cost therapy to large number of older people. Unfortunately, this doesn't work. The results from animal studies and human trials indicate that if there are benefits, they are too small and unreliable to care about. There is something about parabiosis that isn't captured by transfusion.
Otherwise, initial research focused on factors in young blood that might be beneficial. This gave rise to the identification of GDF11 as one such factor, followed by considerable debate over whether this work was flawed, in parallel to the establishment of Elevian, a company that continues to work on therapies based on delivery or upregulation of GDF11. Researchers later provided compelling proof that the effect of beneficial factors in young blood is small in comparison to the effect of harmful factors in old blood, and from there identified TGF-β as one such problem factor. What is suggested here is that parabiosis works via a dilution of harmful factors, not via introduction of youthful factors.
Experiments in diluting blood in old animals with saline, while adding significant amounts of albumin because it cannot be diluted in the bloodstream without severe consequences, seemed to bear out this viewpoint. Animals exhibited similar benefits to those undergoing parabiosis. And yet, is the real signal in the albumin, and not in the dilution? Recently, researchers have delivered albumin to old animals without dilution of blood, and this also produces benefits. So is this a case of albumin becoming modified or damaged in increasing proportions in the bloodstream with advancing age, while cells are very sensitive to that form of damage? This is but the latest twist in this ongoing saga, so perhaps, or perhaps not. Give it a few years, and there may be another chapter to come.
Has the fountain of youth been in our blood all along?
In a series of studies over the last 15 years, researchers have shown that, when infused with blood from young mice, old ones heal faster, move quicker, think better, remember more. The experiments reverse almost every indicator of aging the teams have probed so far: It fixes signs of heart failure, improves bone healing, regrows pancreatic cells, and speeds spinal cord repair. It sounds sensational, almost like pseudoscience. It's some of the most provocative aging research in decades. These studies, which use a peculiar surgical method called parabiosis that turns mice into literal blood brothers, show that aging is not inevitable. It is not time's arrow. It's biology, and therefore something we could theoretically change.
Blood itself will not become a treatment for old age. It's too messy, too complicated, too dangerous. But because of these labs' findings, we know that somewhere swirling around in young veins are signals that awaken the natural mechanisms to repair and restore the body. These mystery factors, once researchers can identify and fine-tune them, could become precious medicine. Heterochronic parabiosis, in which researchers pair two animals at different points in the lifespan, was first used to study aging in the 1950s. But by the 1990s, it was largely forgotten - until more recent studies put it back on the map.
On the theory that blood-borne factors might orchestrate the transitions of aging, researchers turned to heterochronic parabiosis. The team's 2005 findings caused a stir. If an older mouse's leg gets frozen with a piece of dry ice, the cells in charge of muscle repair don't respond much; the number of active cells increases by just 10 percent or so. But after heterochronic parabiosis, twice as many cells activate in response to injury - a reaction like that of a young animal. Older mouse livers demonstrate a similarly sprightly cellular turnover. Longevity enthusiasts eagerly discussed the findings, even though there is little evidence that heterochronic parabiosis extends life; even in rodents, all we know for sure is that it undoes some late-in-life decay.
Meanwhile, a cottage industry began selling young plasma. Around 2016, Ambrosia, a California company, offered to infuse customers as part of a clinical trial that charged participants 8,000 to join. (So far, the team has not published any findings in the scientific literature.) Other entities and individuals launched similar efforts, such as a proposed study that would charge large sums to frail elderly people for doses of young plasma. This "therapeutic plasma exchange" is a legitimate treatment for certain rare autoimmune diseases and problems with coagulation, so these providers are not necessarily required to obtain explicit approval from the Food and Drug Administration so long as they make no unsubstantiated health claims about their regimen. But, of course, they did: Companies marketed benefits for people with memory loss, heart disease, and even Parkinson's. The FDA, now stepping into the regulatory role of the 17th-century pope, released a stern memo in 2019 that curbed the trend.
The most straightforward path to a therapy would be to pinpoint a pro-aging factor in old blood, mouse and human, that a drug could block. Many groups have identified such elements. One has found that a protein called CCL11 increases in aged humans and mice and is correlated with reduced brain cell birth. The other obvious tactic is to identify youthful plasma's secret formula and optimize it. Some research suggests the hormone oxytocin might be a candidate; other work has identified the protein GDF11. Combination therapies are also under consideration; a biotech company is exploring mixtures of hundreds of blood-borne proteins as therapies for a variety of age-related diseases.
It's also possible that the rejuvenating effects seen in experiments don't arise from one magic ingredient, or even from some combination of a dozen or a hundred compounds, but happen simply because the procedure dilutes some unknown harmful substances that accumulate in old blood. From this perspective, there's no particular need for young stuff: Any form of plasma replacement will do. It's sort of like changing the oil in your car. One research group is starting a company and are aiming for human clinical trials to determine if simply flushing out the bloodstream can help with problems like frailty and declining cognition.
Aging as an Emergent Phenomenon, All Trees and No Forest
Theory and modeling dominates the study of the evolution of aging, as is the case in any field in which one is presented with a snapshot of a very complex environment and no ability to conduct directly relevant experiments on that environment. Beyond the state of the natural world here on earth, astrophysics is another good example: a zoo of diverse phenomenon out there in the universe and a great deal of highly mathematical back and forth here on Earth over exactly why the night sky looks the way it does.
Given the nature of the field, any discussion of the fine details of the evolution of aging should be taken as speculative. Evolution as a whole is well supported by the evidence, and a demonstrably useful concept that has informed and accelerated progress in the life sciences. But many of the specific hypotheses and mathematical models that foam and compete under the surface of the bigger picture are likely incorrect in some or all of their details.
The commentary on the evolution of aging in today's open access paper might be taken as the polar opposite of programmed aging hypotheses. Here, aging is envisaged as an inevitable byproduct of the way that natural selection operates, stronger in its effects on early life. Early reproduction is an effective strategy across near all niches, since the occupants of near all niches are affected by predation, disease, and other forms of mortality. Thus mechanisms and systems that aid in early life success at the cost of late life health are selected, despite reducing the hypothetical overall number of offspring that could be produced over a lifetime absent predation, disease, and other extrinsic causes of mortality. Evolution as a process produces imperfect machines, good enough at the outset, but which fall apart thereafter.
Evolution, Chance, and Aging
Evolutionary theory allows for various types of byproduct effects that can affect late life, both negatively and positively. If pleiotropy is viewed mechanistically, molecule-based and network-based pleiotropy make late life effects likely. Research on model systems has already shown that there are a large number of mechanisms by which single mutations can affect late life, supporting the possibility that populations accumulate diverse positive and negative late life effects. It is likely that late life is subject to little selection due to rapidly decreasing population size and lack of late life reproduction in most species, making it unlikely that aging is under simple regulatory control. Instead, it could potentially be an emergent property of the many byproduct effects that affect late life (both selection-based and neutrality-based) and the accumulation of mutations primarily affecting late life. Each species will have its own constellation of byproduct effects and late acting mutations.
This will translate into a large and complex mixture of genetic variation that will distribute across the individuals in populations. Some of the mutations affecting aging may be shared between species, due to conservation of molecules or networks, while others will be species specific. Characteristic lifespans for different species would be another emergent property. Superimposed upon this pattern of aging would be physiological responses to environmental insults common to aging animals, such as stress and infection. Such responses could contribute to the aging pattern. These responses would also consist of both conserved and species-specific components. While it is unclear how age-related tissue dysfunction connects to organism mortality, tissue specific changes with age would be expected to contribute to the species-specific pattern.
One of the most prominent theories accounting for aging and age-dependent mortality rates postulates cumulative damage leading to stochastic failure of tissues and the organism. Specific mechanisms included in this theory are oxidative damage or somatic mutation. The disposability model states that repair capacities are limited by evolutionary constraints, leading to this cumulative damage. At the present time these theories cannot account for the full range of aging patterns in all species. Perhaps aging can be viewed as the net result of hundreds of byproduct effects combined with the accumulation of late-acting mutations, encompassing both positive and negative effects upon mortality and vigor.
Aging is correlated with a large number of species, tissue, and cell type specific changes at the molecular level. It is possible that aging is an emergent property of hundreds of effects, some conserved, some fixed at the species level, and some that are variable at the population level. According to this view, it would only be a modest exaggeration to say aging is all trees and no forest.
Clarifying the Hyperfunction Theory of Aging
My encounters with the hyperfunction theory of aging have at times left me confused, and I suspect that not all of those arguing for it are working from exactly the same picture in their heads. The version presented in today's editorial is somewhat more clear, possibly because the primary intent of the paper is to clarify. It is worth noting up front that the author is very much a proponent of the centrality of mTOR and related signaling pathways in aging, in the sense that aging and age-related degeneration is a program of regulatory change that produces damage. The opposing mainstream viewpoint in the research community is that aging is an accumulation of molecular damage, and regulatory change in signaling pathways is a consequence of that damage.
Hyperfunction is (roughly) the inappropriate continuation of developmental programs past their allotted time, leading to harm to the organism. The author of the editorial below would suggest too much mTOR signaling in later life as a case in point. On the other side of the fence, accumulation of damage is, roughly, the side effect of a metabolism optimized for early life success, lacking long-term repair capabilities, such as the ability to break down persistent cross-links that accumulate only very slowly, or lacking the structural capacity for indefinite function, as is the case for the adaptive immune system, which requires ever more resources devoted to memory.
Both the hyperfunction and damage accumulation views of aging are examples of antagonistic pleiotropy, meaning a given mechanism or system that operates beneficially in youth, and then harmfully in later life. This is the guiding view of the evolution of aging because early reproduction is favored by natural selection. Early reproduction wins the evolutionary niche, up to a point, and therefore there is a race to the lower bound of success, producing organisms optimized to win the competition for early reproduction at the cost of later health. There are counterbalances to the primacy of early reproduction, such as the grandmother effect: our capacity for culture (relative to other primates) has extended human life span (relative to other primates) because grandparents can contribute to the reproductive success of their grandchildren. But on the whole, natural selection favors early reproduction, and builds systems that fall apart once that critical period is done with.
On the topic of the primacy of mTOR and related signaling: I can't say as I think that a central role for mTOR signaling as a rate-limiting cause of aging is a defensible hypothesis given the evidence. It is also not defensible to say that the outcome of the targeted removal of cell and tissue damage in mice suggests that this damage is not life-limiting. Life span in short-lived mammals is very plastic in response to regulatory changes related to the central mechanisms covering cell replication, nutrient sensing, and cell maintenance processes upregulated in response to stresses, such as autophagy. This is not the case in long-lived mammals, as illustrated by the sizable difference in the life extension produced by calorie restriction in mice (as much as 40%) versus humans (a few years at best). While mTOR inhibition has slowed aging to a similar degree to clearance of senescent cells in mice, it hasn't achieved results anywhere near as impressive as clearance of senescent cells when it comes to reversal of specific age-related conditions, such as cardiac hypertrophy. Damage accumulation and repair as rejuvenation after the SENS view of aging looks much more compelling.
The hyperfunction theory of aging: three common misconceptions
The first misconception is that hyperfunction is always an increase of function. Correctly, hyperfunction is often an unchanged function, that is still higher than optimal for longevity. Hyperfunction is a function that was not switched off upon its completion. In some cases, age-related alterations are indeed an absolute increase: hyper-secretory phenotype, pro-inflammation, hypertension, hyperlipidemia, hyperglycemia, hyperinsulinemia, hyperplasia, and hypertrophy of cells and organs (e.g., heart and prostate). In typical cases, hyperfunction is relative. It may even be a decrease of function that is still higher than optimal for longevity in the aging organism.
Using an analogy, consider a car driving 65 miles per hour (mph) on the highway with a 65 mph speed limit. This is the normal and optimal speed on this highway, or optimal functioning early in life. Early in life, during organism growth, all cellular and systemic functions are optimal for growth (not for longevity). However, if the car exits the highway to enter low-speed streets without decreasing speed (stuck accelerator) and continues at the same speed, 65 mph becomes over-speeding, or hyperfunction. The car is bound to crash on your driveway and is destroyed by over-speeding. It has no chance to be destroyed on a molecular level by rusting.
The second misconception is that the hyperfunction theory of aging denies a harmful accumulation of molecular damage. To clarify, molecular damage does accumulate. Furthermore, molecular damage would eventually kill the organism, unless the organism dies from hyperfunctional aging or, even more specifically, from mTOR-driven aging. Aging due to molecular damage and due to cellular hyperfunctions occur in parallel, but the latter is a life-limiting process, which progresses faster. How do we know that hyperfunctional aging is life-limiting and accumulation of molecular damage is not? In several dozen studies, rapamycin (mTORC1 inhibitor) prolonged lifespan in animals. Then mTOR-driven aging is life-limiting almost by definition.
The third misconception is that hyperfunction theory is primarily based on an evolutionary theory. Correctly, the hyperfunction theory is principally based on a cellular model of geroconversion. The hyperfunction theory is not just an evolutionary theory, even though it is completely in agreement with the latter and develops the notion of Antagonistic Pleiotropy (AP) further. Evolutionary perspectives in the hyperfunction theory are needed mostly to explain why hyperfunctional (quasi-programmed) aging is life-limiting and why accumulation of molecular damage is not. Otherwise, the hyperfunction theory is a mechanistic theory: an analogy of the cellular model of geroconversion in vitro. When cells proliferate, mTOR and other growth-promoting signaling pathways drive cellular mass growth, which is balanced by cell division. However, if the cell cycle is blocked by p21 or p16, then the same mTOR pathway drives "pathological growth" (geroconversion) from reversible arrest to irreversible senescence. Geroconversion is a continuation of growth - a quasi-program of growth.
The hyperfunction theory is a translation of the rules of geroconversion to the organism. Organismal aging and geroconversion can be described in similar terms, and similar signaling pathways drive geroconversion and organismal aging. It does not necessarily mean that a few senescent cells cause organismal aging. Fully senescent cells may contribute to aging, but are not required. Instead, most cells are becoming at least relatively hyperfunctional, gerogenic, producing age-related diseases.
On the Benefits of Estrogens in the Context of Longevity Differences by Gender
Why do women tend to live longer than men? There are a good many possible explanations for this well characterized observation. Gender differences in the pace of aging appears to be a robust outcome of the intersection of natural selection with a given mating strategy, but that doesn't say much about the specific mechanisms involved. Sex hormones are the obvious starting point for any investigation of the relevant molecular biology. In humans, estrogen provides a number of physiological benefits in addition to being a sex hormone, and so a higher estrogen level in women is a possible candidate mechanism.
The tudy reported in today's open access paper is an interesting examination of some of the outcomes on metabolism in women who undergo induced menopause followed by estrogen replacement therapy. The effects of these changes are so sweeping that it is hard to separate those relevant to aging: evidence tends to be more suggestive than conclusive in this sort of investigation. No one study will be compelling on its own. The weight of literature does lean in the direction of a sizable role for estrogen in determining a slower pace of aging in women versus men, however.
Estrogen Replacement Therapy Induces Antioxidant and Longevity-Related Genes in Women after Medically Induced Menopause
The great increase in average life expectancy during the 20th century emerges as one of society's greatest achievements. As a matter of fact, in the last two decades, life expectancy at birth has increased by 5-10 years. Regardless of the cultural or socioeconomic context, women have lived longer than men in different countries and in every era. Nowadays, 75% and 90% of people older than 100 years and 110 years (respectively) are women, and the longest living centenarian person (122 years old) was a woman. This phenomenon occurs not only in humans, but in many species, like all Old-World monkeys, apes, short-finned pilot whales, African lions, red deer, and Wistar rats, in which female life expectancy exceeds male life expectancy by 16%.
One plausible explanation for this protection against aging is that females are endowed with higher levels of estrogens than males. Estrogens are known to have many beneficial effects: cardioprotection, skeletal homeostasis maintenance, brain function, and hematopoietic stem cell division enhancement, among others. Moreover, intramuscular estrogen levels have been recently associated with skeletal muscle strength and power. Furthermore, they act as antioxidants in vitro and also have beneficial effects against oxidative stress in vivo. Indeed, a few years ago, we reported that estrogens were able to induce antioxidant and longevity-related genes, such as glutathione peroxidase (GPx) and manganese superoxide dismutase (Mn-SOD) in rats, through a mechanism involving the ERK1-2/NFκB pathway. We thus suggested that this finding could explain why females suffer less oxidative stress than males in many species, including humans.
However, all these estrogen beneficial effects may be lost in menopause. Indeed, we observed that when mimicking postmenopausal loss of estrogens by ovariectomizing Wistar rats, their peroxide production rose, and their glutathione levels decreased. They were restored after estrogen replacement therapy. This confirmed the impact of estrogen as a causative agent for this effect and made us hypothesize that this finding could be extrapolated to humans, that is, that estrogen replacement therapy (ERT) may be useful to restore estrogen levels and thus the estrogen-related beneficial effects.
Thus, the aim of this study was to confirm the ability of estrogens to upregulate antioxidant and longevity-related genes in humans, particularly in women, after a medically induced menopause. As expected, we found that medically induced menopause significantly decreased sexual hormone (estrogens and progesterone) levels. It also lowered glutathione peroxidase (GPx), 16S rRNA, P21, and TERF2 mRNA expression and blood glutathione levels. Estrogen replacement therapy significantly restored estrogen levels and induced mRNA expression of Mn-SOD, GPx, 16S rRNA, P53, P21, and TERF2 and restored blood gluthatione levels. Progesterone replacement therapy induced a significant increase in MnSOD, P53, sestrin 2, and TERF2 mRNA expression when compared to basal conditions. These findings provide evidence for estrogen beneficial effects in upregulating antioxidant and longevity-related genes in women.
Better Mapping Age-Related Changes in the Human Gut Microbiome
In today's open access paper, researchers report on an improved mapping of changes in microbial populations in the gut with advancing age. Past studies have shown that significant changes start comparatively early, in the mid-30s, for reasons yet to be clearly understood. Age-related changes in diet (generally worse) and exercise (generally lessened) clearly play a role, but at the high level, the most important changes are thought to be the result of a bidirectional interaction between the immune system and the microbiome. Growing numbers of inflammatory microbes contribute to the harmful chronic inflammation of aging, expanding their populations at the expense of beneficial microbes that generate useful metabolites. Meanwhile, the age-related decline of immune function, partially caused by chronic inflammation, means that harmful microbes are less effectively suppressed, enabling their expansion in the intestinal tract.
The novel results in this work include a link between medication status in later life and changes in the gut microbiome. Most older people take one or more medications for chronic conditions. This is quite interesting and a topic that has gone largely untouched to date in investigations of how the microbiome interacts with health in later life. Given the influence of the gut microbiome on systemic inflammation, and noting that inflammation is of great importance in aging and age-related disease, this sounds like one more good reason to push for the widespread clinical use of fecal microbiota transplantation and other approaches shown to improve the quality of the aged gut microbiome.
This study examines how the duodenal microbiome changes with chronological age and with the process of aging. In this article, we have used the term aging to include chronological age, the number of concomitant diseases, and the number of medications used. Our results indicate that the duodenal microbiome changes progressively and significantly in older subjects, including a decrease in microbial diversity that was driven not only by chronological age but also by increases in the number of medications used and the number of concomitant diseases. Furthermore, this decrease in diversity is associated with increases in coliform levels. Representatives from phylum Firmicutes demonstrate stability and predictability over time, but other components of the common core duodenal microbiome change significantly with chronological age. This was driven by increases in phylum Proteobacteria, which increases to the second most abundant phylum in the duodenum in adults aged 36-50 years and remains in this position throughout adulthood. In contrast, phylum Bacteroidetes progressively decreases in RA with increasing age. The increase in RA of phylum Proteobacteria results from increases in the family Enterobacteriaceae, and specifically the genera Escherichia and Klebsiella. These changes are most pronounced when comparing young adults in their 20s and 30s to adults in their 70s and beyond, and correlated with changes in predicted microbial metabolic pathways, including the ubiquinone biosynthesis pathway, which is an antioxidant pathway whose expression is increased under stress conditions, including in anoxic environments for Escherichia coli.
We identified a significant decrease in duodenal microbial diversity in older subjects, which is consistent with previous data demonstrating reductions in microbial diversity in the stool microbiome with age, coupled with shifts in the dominant species and declines in beneficial microorganisms. However, advancing chronological age is accompanied by multiple factors that complicate microbial analysis. For example, the process of aging is associated with increases in the number of concomitant diseases present in older subjects and the number of medications used, factors that were not explored in previous studies. Through multivariate analyses controlling for these factors, we found that the decrease in duodenal microbial diversity was driven by a combination of chronological age, increases in the number of concomitant diseases, and increases in the number of medications used by older subjects, rather than solely by age alone. Our culture findings indicate that this decrease in microbial diversity in the duodenum is also associated with increased levels of coliform bacteria in the duodenum. This included increased relative abundance of the genera Klebsiella and Escherichia, a finding that is also consistent with previous findings in studies using stool, but here we show that Escherichia is associated with chronological age rather than the aging process, and that Klebsiella is associated with the number of medications used.
Previous studies have shown that the stool microbiome is dominated by bacteria from the phyla Firmicutes and Bacteroidetes. We found that the common core microbiome in the duodenum is also dominated by phylum Firmicutes, including the genera Streptococcus and Veillonella which are part of the core of the duodenal microbiome, but the relative abundance of the other major phyla differ with increasing age, including decreased relative abundance of Bacteroidetes, which is consistent with recent findings from the stool microbiome. These changes appear to be driven by increases in phylum Proteobacteria, which significantly and negatively affects the relative abundance of the phyla Firmicutes and TM7. Within phylum Proteobacteria, changes in the family Enterobacteriaceae also significantly and negatively impact the duodenal microbiome, affecting both the relative abundance of other microbial families and overall microbial diversity. These increases in Enterobacteriaceae were driven by the genera Escherichia and Klebsiella, both of which are coliforms, again supporting a link between increases in duodenal coliforms and decreased microbial diversity in older adults.
Further comparisons between the youngest and oldest groups of adults (ages 18-35 and 66-80 years, respectively) revealed that the changes in some genera were solely associated with chronological age (e.g., Escherichia, family Enterobacteriaceae), whereas others were in fact associated with the number of medications used (e.g., Klebsiella, family Enterobacteriaceae) or with the number of concomitant diseases (e.g., Clostridium, family Clostridiaceae). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of predicted microbial metabolic pathways based on 16S data suggested enrichment of microbial genes associated with the ubiquinone biosynthesis pathway in the duodenal microbiome of older adults. Ubiquinone constitutes the first line of defense in oxidative stress and plays an essential role in respiration in E. coli, so it is not surprising that this pathway could be enriched in older subjects.
In conclusion, this study examined how age and the process of aging are associated with changes in the microbiome of the small intestine, using validated sampling and processing techniques. The most significant differences are higher relative abundance of the phylum Proteobacteria and decreased relative abundance of Bacteroidetes in older subjects when compared to the youngest group. The higher relative abundance of Proteobacteria appeared to affect other duodenal microbial taxa, leading to decreased microbial diversity and increased relative abundance of coliforms and of anaerobic bacteria. The small intestine is vital to digestion, nutrient absorption, and incretin regulation, and consequently has a critical effect on host metabolism. The small intestine microbial changes reported here may play a clinically relevant role in human health and disease throughout the aging process. Further studies are needed to understand the causes and implications of these microbial changes with advancing age.
Well Structured Cartilage Grown from Embryonic Stem Cells
Tissue engineering of new cartilage is an important goal in the field of regenerative medicine, but it has proven challenging to obtain the necessary structural properties. Natural cartilage is a resilient, strong tissue. Incremental progress towards this goal has been made over the years, as researchers explored the space of the possible. Now we see demonstrations such as the one noted here, in which sizable sections of engineered cartilage can be produced from embryonic stem cells, and the tissue exhibits the desired structural properties. If this can be achieved with embryonic stem cells, then it can in principle also be achieved with induced pluripotent stem cells, either generated from a patient cell sample, or made universal by knocking out MHC class I and II receptors and other immune-related signals in order to be used in any patient without rejection.
Articular cartilage functions as a shock absorber and facilitates the free movement of joints. Currently, there are no therapeutic drugs that promote the healing of damaged articular cartilage. Limitations associated with the two clinically relevant cell populations, human articular chondrocytes and mesenchymal stem cells, necessitate finding an alternative cell source for cartilage repair. Human embryonic stem cells (hESCs) provide a readily accessible population of self-renewing, pluripotent cells with perceived immunoprivileged properties for cartilage generation.
We have developed a robust method to generate 3D, scaffold-free, hyaline cartilage tissue constructs from hESCs that are composed of numerous chondrocytes in lacunae, embedded in an extracellular matrix containing Type II collagen, sulphated glycosaminoglycans and Aggrecan. The elastic (Young's) modulus of the hESC-derived cartilage tissue constructs (0.91 ± 0.08 MPa) was comparable to full-thickness human articular cartilage (0.87 ± 0.09 MPa). Moreover, we have successfully scaled up the size of the scaffold-free, 3D hESC-derived cartilage tissue constructs to between 4.5 mm and 6 mm, thus enhancing their suitability for clinical application.
Treadmill Training for Old Mice Upregulates Autophagy and Improves Heart Function
It is well demonstrated that structured exercise programs improve function and reduce mortality in old humans, in part because the majority of people do not undertake anywhere near enough exercise. For mice, more activity takes place into later life, but how much is quite dependent on the environment in which they are housed. Looking at the study here, I would expect this to be a comparison of exercise trained mice with untrained mice that are less active than they would be if given options such as an exercise wheel. That may be a better match to the human situation than the other options. While looking at the results, it is worth recalling that past data shows that exercise interventions improve healthspan but not lifespan in mice. It isn't as effective as calorie restriction in this regard.
Protein quality control mechanisms decline during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs. adult mice.
As expected, 24-month-old male C57BL/6J mice (old) exhibited repressed autophagosome formation and protein aggregate accumulation in the heart, systolic and diastolic dysfunction, and reduced exercise capacity vs. 8-month-old (adult) mice. To investigate the influence of late-in-life exercise training, additional cohorts of 21-month-old mice did (old-ETR) or did not (old-SED) complete a 3-month progressive resistance treadmill running program. Body composition, exercise capacity, and soleus muscle citrate synthase activity improved in old-ETR vs. old-SED mice at 24 months. Importantly, protein expression of autophagy markers indicate trafficking of the autophagosome to the lysosome increased, protein aggregate clearance improved, and overall function was enhanced in hearts from old-ETR vs. old-SED mice.
This data provides the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and contractile performance in mouse hearts.
Radiation Treatment Persistently Alters Heart Cell Function to Produce Benefits in Heart Failure Patients
This paper is interesting as a first step on the way to further research into compensatory therapies that can reduce the cardiac muscle dysfunction of heart failure. One-time radiation therapy appears to persistently change cardiomyocyte behavior via altered epigenetic regulation of notch signaling, leading to modestly improved heart tissue function. Perhaps this should be taken as supportive of efforts to more directly target this regulatory pathway in the aging heart via other means.
Cardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in NaV1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to NaV1.5 upregulation after RT.
Our study presents findings to suggest that radiation therapy, successfully used in patients with refractory VT, may increase levels of the cardiac sodium channel and improve conduction. Indeed, explanted cardiac specimens obtained from a treated patient with refractory VT revealed threefold higher NaV1.5 protein levels in the radiation-targeted region when compared to a nontargeted region of the same heart, restoring NaV1.5 to levels within the range of nonfailing myocardium. As an observation of the potential effect of RT on human physiology, we also report a non-significant decrease in mean QRS duration in the Electrophysiology-guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia (ENCORE-VT) patient cohort, as well as robustly shortened QRS intervals in at least 4 of the 19 patients.
Our findings have direct relevance for patient care. Most surviving patients continue to exhibit reduced VT burden 24 months after a single RT treatment. Our results demonstrate that the functional and molecular effects of RT and Notch reactivation are persistent and expected to directly translate into long-term durability of therapy.
How Much of the Benefit of a Healthier Diet is Due to Natural Calorie Restriction Mimetics?
How much of the benefit of a healthier diet arises from the effects of natural calorie restriction mimetic compounds? That question is an interesting one from a scientific perspective, but the answers are probably not all that valuable in a practical sense. We have a fairly good idea as to the size of the benefits to long-term health obtained via a better diet, and separately by eating less of that diet, the practice of calorie restriction while still obtaining sufficient micronutrients. Calorie restriction mimetic compounds trigger some of the same beneficial cellular stress response mechanisms as does a low calorie diet, though in lesser and more piecemeal ways. Knowing more about how and why a better diet is a better diet isn't the path to large improvements in human longevity, but it is a fascinating subject, nonetheless.
In addition to genetic, environmental and lifestyle factors, nutrition plays a vital role in shaping health throughout human aging. Recently, health was defined as the sum of several hallmarks, including, the ability to react to environmental and cellular stress, integrity of barriers and maintenance of cellular and organismal homeostasis, of which many cross-talk with dietary factors. While a moderate consensus has been reached on what defines an unhealthy diet, the constitution of a healthy diet remains debated and subject to different beliefs. In principle, healthy diets should have positive effects on diverse health parameters, while not evoking negative effects. Different concepts of healthy dietary plans have been developed. These indices estimate and rate the intake of 8-12 components (for instance whole grain, nuts, legumes, fruit, vegetable, alcohol, etc.) and good scores are linked to lower cardiovascular disease (CVD) incidence and cancer mortality.
Accumulating evidence suggests that caloric restriction (CR) and various forms of fasting (intermittent fasting, time restricted eating, periodic fasting), avoiding malnutrition and including an adequate intake of macro- and micronutrients, present yet additional possibilities to promote the health status by reducing CVDs and cancer, among other beneficial effects. Recently, the concept of caloric restriction mimetics (CRMs) was developed to describe pharmacologically active substances that mimic some of CR's myriads of effects. At the core of the CRM definition, we and others argue that potential CR-mimicking compounds should in principle increase life- and/or healthspan and ameliorate age-associated diseases in model organisms, thus often the simultaneous use of the term "anti-aging substances." Additionally, CRMs should be capable of inducing autophagy, a homeostasis-regulating cellular recycling mechanisms that degrades obsolete, damaged or otherwise unneeded proteins, cellular structures or organelles.
Natural CRM candidates are widely present in foods and, in most cases, inevitably consumed by humans. Given their prominent occurrence in plant-based foods (especially polyphenols and polyamines), it is conceivable that these compounds contribute to the beneficial effects of healthy diets. Nevertheless, to date, specific dietary recommendations must be read with caution as too many uncertainties remain regarding bioavailability, concentration in food, stability and optimal intake levels. Furthermore, estimations of CRM levels in healthy diet plans are largely elusive and should be evaluated in future studies, as they could add to or be responsible for some of the beneficial effects of these diets.
Overall, the promising and emerging field of dietary CRM candidates needs to be considered with scientific rigor, as large parts of evidence on their effects in humans come from epidemiological and/or small-scale studies, often conducted with plant-based extracts that contain numerous bioactive substances. Problems may also arise when translating pre-clinical and epidemiological evidence of dietary and body-endogenous substances to clinical studies. For many of the herein discussed substances important data yet need to be collected: oral bioavailability, stability throughout the intestinal tract, metabolization, cellular uptake, distribution throughout the body, organ-specific effects, interaction with body-endogenous biosynthesis pathways and bioactive levels, just to name a few. More importantly, epidemiological data on dietary components can only be as good as the underlying food databases. Unfortunately, regionally varying food compositions, quality, the influence of meal preparation techniques and storage conditions are sometimes insufficiently studied or documented.
Icariin Treatment Improves the Aging Gut Microbiome in Mice
The gut microbiome is important in health and aging. Populations of microbes change with age, favoring harmful inflammatory populations at the expense of populations that generate beneficial metabolites. Restoration of a youthful microbiome via fecal microbiota transplantation has been demonstrated to be beneficial in animal studies. The research community is also evaluating other approaches to at least partially rejuvenate the aged gut microbiome, such as flagellin immunization to provoke the immune system into removing more of the harmful gut microbes. Researchers here provide evidence for treatment with icariin, a plant-derived flavonoid, to favorably adjust the balance of intestinal microbial populations in mice, though it is unclear as to the mechanism of action.
We previously reported the neuroprotective effects of icariin in rat cortical neurons. Here, we present a study on icariin's anti-aging effect in 24-month aged mice by treating them with a single daily dose of 100 mg/kg of icariin for 15 consecutive days. Icariin treatment improved motor coordination and learning skills while lowered oxidative stress biomarkers in the serum, brain, kidney, and liver of the aged mice. In addition, icariin improved the intestinal integrity of the aged mice by upregulating tight junction adhesion molecules and the Paneth cells and goblet cells, along with the reduction of iNOS and pro-inflammatory cytokines (IL-1β, TNF-α, IL-2 and IL-6, and IL-12). Icariin treatments also significantly upregulated aging-related signaling molecules, Sirt 1, Sirt 3 and Sirt 6, Pot1α, BUB1b, FOXO1, Ep300, ANXA3, Calb1, SNAP25, and BDNF in old mice.
Through gut microbiota (GM) analysis, we observed icariin-associated improvements in GM composition of aged mice by reinstating bacteria found in the young mice, while suppressing some bacteria found in the untreated old mice. To clarify whether icariin's anti-aging effect is rooted in the GM, we performed fecal microbiota transfer (FMT) from icariin-treated old mice to the old mice. FMT-recipients exhibited similar improvements in the rotarod score and age-related biomarkers as observed in the icariin-treated old mice. Equal or better improvement on the youth-like features was noticed when aged mice were FMT with feces from young mice. Our study shows that both direct treatments with icariin and fecal transplant from the icariin-treated aged mice produce similar anti-aging phenotypes in the aged mice. We prove that GM plays a pivotal role in the healing abilities of icariin. Icariin has the potentials to be developed as a medicine for the wellness of the aged adults.
Preprint of the Paper Summarizing the Leucadia Therapeutics Hypothesis and Evidence on the Cause of Alzheimer's Disease
The Leucadia Therapeutics staff has been working for a few years now to prove the founder's hypothesis on the cause of Alzheimer's disease. In this view, the primary problem is impaired drainage of cerebrospinal fluid. As the drainage path through the cribriform plate is blocked by slow ossification of channels, metabolic waste builds up in the olfactory bulb, the closest region of the brain. This is where Alzheimer's pathology initially starts, before spreading. The team has gathered an imposing amount of human anatomical data, and their eventual goal is to unblock the drainage path via an implant placed in the cribriform plate.
Cerebrospinal fluid (CSF) clears the brain's interstitial spaces, and disruptions in CSF flow or egress impact homeostasis, contributing to various neurological conditions. Here, we recast the human cribriform plate from innocuous bony structure to complex regulator of CSF egress with an apical role in Alzheimer's disease etiology. It includes the pathological evaluation of 70 post-mortem samples using high-resolution contrast-enhanced micro-CT and cutting-edge machine learning, a novel ferret model of neurodegeneration, and a clinical study with 560 volunteers, to provide conclusive evidence of a relationship between cribriform plate aging/pathology and cognitive impairment.
Interstitial spaces within the medial temporal lobe and basal forebrain are cleared by CSF flow that drains through olfactory structures to the olfactory bulb, directly above the cribriform plate. We characterized CSF flow channels from subarachnoid spaces under the olfactory bulb to the nasal mucosa through subarachnoid evaginations that subdivide into tiny tubules that connect to an elaborate conduit system within the cribriform plate. These conduits form an internal watershed that runs from the crista galli's vault to a bony manifold within the olfactory fossa's back wall, connecting with large apertures in between.
We found that the cross-sectional area of apertures limits CSF flux through the cribriform plate, which declines with increasing age. Subjects with a confirmed post-mortem diagnosis of Alzheimer's disease had the smallest CSF flux capacity, which reduces CSF-mediated clearance in upstream areas and leads to the accumulation of toxic macromolecules that seed AD pathology.
We surgically occluded apertures in adult ferrets and found that this manipulation induced progressive deficits in spatiotemporal memory and significant atrophy of the temporal lobe, olfactory bulbs, and lateral olfactory stria. Finally, we explored human cribriform plate aging/pathology and cognition in a clinical study with 560 participants (20-95 years old). We evaluated cribriform plate morphology with CT and Deep Learning, assessed memory with a novel touch screen platform, tested olfactory discrimination, and asked questions about family history and relevant life events, like broken noses. Deep learning algorithms effectively parsed subjects and established the feasibility of predicting Alzheimer's disease years before a clinical presentation of cognitive impairment.
Longevity Science Foundation Commits to 1 Billion in Research Funding Over the Next Decade
The inaugural press release from the Longevity Science Foundation touts their commitment to put 1 billion over the next ten years into research aimed at extending the healthy human lifespan, but is light on details as to where the funding is coming from. It is unclear as to how aspirational versus actual this is. That said, the people involved are serious and successful scientist and entrepreneurs in the field, so we shall see. It is certainly the case that more sizable initiatives are needed, as well as more initiatives devoted to projects focused on the biotechnologies of rejuvenation, and not merely efforts to reproduce the effect of exercise or calorie restriction. Given the vast ongoing toll of suffering and death caused by aging, there is room for far more research and development funding than is presently devoted to this cause.
A consortium of biotech founders, clinicians, and leading longevity research institutions announced today the launch of the Longevity Science Foundation. The new Swiss foundation has committed to distributing more than 1 billion over the next ten years to research, institutions and projects advancing healthy human longevity and extending the healthy human lifespan to more than 120 years. The Longevity Science Foundation will provide funding to promising longevity research institutions and groups around the world. The focus of the Foundation will be to select support projects in four major areas of healthy longevity medicine and tech - therapeutics, personalised medicine, AI, and predictive diagnostics. The Foundation is seeking to fund projects that can make a significant difference in people's lives as soon as possible - even within five years.
One of the main focuses of the Foundation is in driving longevity medicine from theoretical concepts to real-world applications. The Foundation's donations will support the transformation of scientific findings and deep technological advances into treatments and solutions that can be used in the clinic today. By identifying and funding the most promising and cutting-edge advances, the Foundation seeks to address one of the most pressing issues in the science and applicability of longevity medicine - radical inequality in accessing and understanding longevity-focused treatment. Significant funding gaps remain an obstacle to bringing longevity medicine out of the laboratory and into the real world.
Age versus Frailty as a Predictor of Mortality
A number of companies and research groups are performing drug discovery by using effects on frailty in mice as a readout. To what degree is frailty an adequate measure of the harms done by aging? One way to answer that question is to assess mortality in a human study population against a measure of frailty, with and without factoring in chronological age. Researchers here show that frailty is a fair marker for age-related mortality, but it is not a reflection of every degenerative, harmful process taking place under the hood. Frailty and age combined provide a better correlation with mortality than frailty alone, indicating that there are aspects of age-related decline that contribute meaningfully to mortality without producing evident frailty.
As populations get older, the association between chronological age and health status becomes increasingly heterogeneous. To describe this heterogeneity in health status as we age, the concepts of biological age or frailty versus fitness spectrum have been proposed. The frailty index (FI) methodology was introduced to quantify the accumulation of people's health 'deficits' (i.e., symptoms, clinical signs, medical conditions and disabilities) at a given chronological age. This method has allowed for the establishment of potentially useful population norms and the study of influences of wider determinants of health on the variation in health status within people of a similar chronological age.
Since FI deficits increase with age, the FI has a statistically significant association with chronological age. However, on the account of population heterogeneity, the effect size of this association has been found to be small. It has been suggested that given the age-related nature of its constituent deficits, the FI should be interpreted jointly with age. Our aim was to utilize data from 8,174 wave 1 participants in The Irish Longitudinal Study on Ageing (TILDA) to conduct, separately by sex, supervised machine learning analyses of the ability of the individual items of an FI to predict 8-year mortality. To gain insights as to the importance of age in this prediction, we repeated the analyses including age as a feature.
By wave 5, 559 men and 492 women had died. In the absence of age, the FI was an acceptable predictor of mortality with area under the curve (AUCs) of 0.7. When age was included, AUCs improved to 0.8 in men and 0.9 in women. After age, deficits related to physical function and self-rated health tended to have higher importance scores. Not all FI variables seemed equally relevant to predict mortality, and age was by far the most relevant feature. Chronological age should remain an important consideration when interpreting the prognostic significance of an FI.
Senescent Mesenchymal Cells Cause Localized Inflammation in Osteoarthritic Cartilage
Given the failure of a locally injected senolytic drug to make a meaningful impact in osteoarthritis, the present consensus at the senolytics end of the longevity industry appears to be that systemic inflammatory signalling from senescent cells elsewhere in the body outweighs the contribution of local senescent cells in osteoarthritic joints. But perhaps the senolytic drug used in the failed trial was not a good candidate for humans; it remains to be seen as to whether better outcomes can be produced by systemic senolytic approaches in clinical trials for osteoarthritis. Meanwhile, researchers here suggest that there is in fact a meaningful contribution to harmful inflammation arising from senescent cells in osteoarthritic cartilage, and propose that the nature of the senescent cell population may explain some of the apparently contradictory past results.
Although osteoathritis (OA) was considered as a non-inflammatory disease, an ever-increasing body of evidence suggests that chronic degeneration of the joint is associated with persistent long-term low-grade inflammation in the joint. The source of inflammation in OA is unknown, although it has been shown to associate with high-fat diet, mechanical injury, and aging. We have shown here that one of the sources of joint inflammation is mesenchymal stromal cells (OA-MSC) within cartilage itself. OA-MSC synthesizes pro-inflammatory cytokines and chemokines that have been implicated in OA pathogenesis. We demonstrated that the induction of such pro-inflammatory molecules occurs at both mRNA and protein levels. We have also shown that the induction of inflammation in OA cartilage occurs during the transition from normal cartilage stromal cell (NCSC) in the young to the OA-MSC in the old during aging.
In recent years, cell senescence has been shown to be closely associated with OA pathogenesis. Injection of senescent cells into the joint space led to joint degeneration. Conversely, local clearance of p16INK4a-positive senescent cells from the joint attenuated injury and aging induced OA. Although the role of senescent cells in causing joint degeneration has been established, the molecular mechanism by which a chondrocyte reaches senescence has not been well understood. The expression levels of the cell senescence marker p16INK4a and senescence-associated secretory phenotype (SASP) were elevated in the serial passages of human chondrocyte culture in vitro and in aged human and mouse cartilage in vivo. However, inactivation of p16INK4a in chondrocytes of adult mice failed to attenuate joint degeneration during aging or injury. This observation raised an important question whether senescent chondrocytes were involved in cartilage degeneration.
We have shown here for the first time that OA-MSC, but not OA chondrocytes (OAC), has elevated levels of p16INK4a and SASP. Therefore, OA-MSC, but not OAC, are the senescent cells that become a source of inflammation in the joint. Our study also provided a plausible molecular explanation to the observation that joint degeneration was not affected when the p16INK4a gene was deleted in chondrocytes. Since p16 is expressed at very low levels in the OAC, targeting OAC for p16 knockout might not affect the real source of cell senescence in OA cartilage. Our data predict that joint degeneration would be attenuated if p16 were knocked out in OA-MSC, since it would abolish the source of SASP in OA cartilage. Although this prediction remains to be tested, OA-MSC should be considered as potential target cells of senolytics and anti-inflammation therapy for OA intervention in future studies.
More on NeuroD1 Gene Therapy to Restore Neural Function Following Injury and Scarring
You might recall that researchers have been working on the direct conversion of glial cells in the scars produced following ischemic injury to the brain. Overexpression of NeuroD1 via gene therapy appears an effective approach to achieve this goal, at least in the controlled scenario of an animal model. In mice this intervention gives rise to neurons that integrate into existing neural circuits, leading to some degree of functional recovery.
We demonstrated that NeuroD1-mediated in vivo direct reprogramming of astrocytes into neurons promoted their neural circuit integration and led to the visual functional recovery after ischemic injury. Our work bridged the knowledge gap between individual cellular response recovery and animal behavioral recovery, where we characterized the functional synapses formed from specific projections and assessed neuronal response to stimuli in awake mice, which are critical functional characterization at the intermediate neural circuit level. The mouse primary visual cortex is a unique model system providing an opportunity to quantify projection-specific functional connectivity and the direct visual responsiveness of the reprogrammed cells. Furthermore, the ability to record responses to different visual features such as orientation and direction provides a unique ability to quantify how well the cells mature and whether the synapses they receive are functional.
In our model system, the visual responses were drastically reduced following ischemic injury, yet they recovered following the NeuroD1 delivery. The putative excitatory neurons started to regain their visual responses 3 weeks after reprogramming, while the putative inhibitory neurons progressively integrated circuit inputs and refined their activity over a longer period of time. This delayed recovery of inhibition after reprogramming is similar to the absence of matured inhibition at an early age. Furthermore, these visual responses became more specific with time, based on our two-photon calcium imaging and extracellular recording results. The NeuroD1 converted cells gradually developed to be selective to the orientations and directions of visual stimuli, which is a typical feature of the mature visual cortical neurons. Interestingly, the reprogrammed cells at 6 weeks post-infection demonstrated higher selectivity compared to the healthy controls, which could be potentially explained by the more functionally developed synaptic inputs received by the reprogrammed cells compared to the healthy controls.
Compared to other studies, the functional recovery achieved by NeuroD1-mediated astrocyte-to-neuron conversion in vivo was similarly efficient. The local functional circuit and visual response recovery were also similar to embryonic neuronal transplantation results. Direct in vivo conversion of astrocytes into neurons removes the possibility of graft rejection and provides a viable solution for this problem, however. Our findings suggest that the NeuroD1-based in vivo direct reprogramming technology may be a promising gene therapy treatment of brain injury by replenishing the lost neurons and successfully integrating them into the existing neural circuit.