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Advice on How to Think About Epigenetic Clocks and their Utility
https://www.fightaging.org/archives/2024/08/advice-on-how-to-think-about-epigenetic-clocks-and-their-utility/
Epigenetic patterns of gene expression regulation change with age in distinct ways, and so it is possible to use machine learning to produce algorithmic combinations of this data that reflect chronological age and biological age. There are any number of such algorithms, and so there are many epigenetic clocks now, with more are being produced every year. These are now accompanied by clocks derived from other omics data, alongside clocks built from combinations of simple measures such as grip strength, gait speed, and so forth. It is commonly accepted, and evidence supports this hypothesis, that when a clock predicts an age higher than an individual’s chronological age, this age acceleration is an indication of a greater burden of age-related damage and dysfunction.
None of this tells us how underlying damage and dysfunction produces the observed changes in clock data, for any of the clocks built from omics data. This is a problem, because absent this understanding one can’t rely upon a clock to produce the right answer when it is used to assess the results of a potential rejuvenation therapy. For example, senolytic treatments clear senescent cells and reduce their impact on metabolism, but it is by no means a given that any given epigenetic clock is actually measuring that effect. Or perhaps the clock is overly reliant on that effect, and will therefore overestimate the benefit of removing senescent cells. Without, at minimum, calibrating a clock to the specific treatment in mouse life span studies one can’t know.
Further, different tissues exhibit different patterns of omics data change with aging. Yet most clocks use blood samples, assessing biological age from immune cell populations. So how should researchers think about epigenetic and other omics clocks in the context of their work? Today’s open access commentary is, I think, a useful summary of some of the present wisdom on this topic. Acceptance of the inherent limitations (for now, at least) and avoidance of generalizing results from blood markers given the large variance between tissues sounds like good advice.
Recalibrate concepts of epigenetic aging clocks in human health
First, epigenetic aging in human health should be viewed holistically. The relationship between epigenetic age and health outcomes is often viewed through a narrow lens. Blood epigenetic clocks are predominantly used due to their availability. However, as measured by these clocks, studies and trials frequently focus solely on blood, neglecting broader aging effects on the entire organism. This oversight can lead to exaggerated claims and misconceptions among the public. A younger biological age based on a buccal swab does not necessarily equate to a younger immune system or skeletal muscle composition.
Second, accept the limitations of epigenetic aging clocks. While efforts have been made to develop clocks independent of tissue or cell type, our study demonstrates that entirely eliminating the confounding effects of cell type in epigenetic age acceleration calculation is nearly impossible. Senescence at the cellular level manifests differently across cell types and states, making it challenging to devise a single clock applicable to all cell types. Although universal epigenetic aging marks may exist, modeling them accurately across cell types at the bulk tissue level is complicated by age-related changes in cell composition.
Third, contextualize when interpreting epigenetic aging results. The perception that an accelerated epigenetic age is always detrimental stems from a limited understanding of the clock mechanism. Contrary to this notion, multiple studies have documented beneficial outcomes in specific groups of cancer patients with accelerated epigenetic age. Immune responses play a pivotal role in cancer patient outcomes, and the connection between immune cell composition and epigenetic age established in our study sheds light on how epigenetic age acceleration affects these outcomes, especially in treatments like chemotherapy, radiation therapy, and immunotherapy that influence or rely on the immune system. Moreover, research has revealed significant daily oscillations in epigenetic age, mirroring changes in immune cell composition over the circadian rhythm.
Fourth, model epigenetic biomarkers on biological pathways to avoid black boxes. While direct modeling of DNA methylation changes with age enhances the predictability of biological age, it often obscures specific pathways captured by the algorithm, resulting in black boxes. To mitigate this, further efforts should focus on directly modeling aging and senescence-related pathways for novel biomarkers tracing age. Several markers exemplify the value of this approach. EpiTOC, for instance, functions as a mitotic clock, estimating stem cell divisions. It tracks age and correlates with increased cancer risk, offering insights into the association between cellular aging processes and cancer.
A Baby and Bathwater Argument for Geroscience Research and Development to be the Wrong Direction
https://www.fightaging.org/archives/2024/08/a-baby-and-bathwater-argument-for-geroscience-research-and-development-to-be-the-wrong-direction/
How much of academia and industry is headed in the wrong direction in the matter of treating aging as a medical condition, working on projects that are unlikely to produce meaningful extension of human life span? I am largely in agreement with the author of today’s open access paper, at least to the point of saying that a large fraction of projects cannot and will not move the needle on human life span, and that likely includes near everything commonly grouped under the heading of geroscience. That means calorie restriction mimetics, autophagy upregulation, small molecules that improve mitophagy, and so forth. These largely pharmacological approaches are unified in their inability to improve on the effects of exercise, where tested in humans, with very few exceptions (e.g. rapamycin).
I concur with the author’s argument that the 1990s studies that launched the modern interest in treating aging and extending human life did not actually indicate the right way ahead. This has long been remarked upon, and coming to be taken for granted, in at least some parts of the longevity community. All of the early, low hanging fruit interventions that slowed aging in short-lived species make use of mechanisms related to the calorie restriction response, and do not meaningfully extend life in long-lived species. When it comes to surviving seasonal famine, only the short-lived species must evolve a sizable plasticity of life span. A season is a long time to a mouse, not so much to a human.
The greatest progress that has taken place towards viable treatments for aging did not build upon the early discoveries of single gene mutations that extended life in laboratory species, but happened as a result of a broadening of investment in the field into other lines of research. But in my view, unlike that of the author of the commentary, that expansion of research and development has in fact led to important approaches that seem quite likely to be useful. In particular those grouped under the Strategies for Engineered Negligible Senescence (SENS), or repair viewpoint of aging, in which one identifies specific fundamental, driving forms of cell and tissue damage and repair them. This stands in stark contrast to the geroscience viewpoint in which one adjusts metabolism to slow aging, i.e. slow the accumulation of cell and tissue damage.
Good scientists tend not to make good engineers (and possibly vice versa); the mindset needed is quite different. The scientific viewpoint is the drive for complete understanding, with only a grudging, reluctant forking of an ongoing research process into to the parallel process of using knowledge to build technology. The engineering viewpoint, on the other hand, is focused on making empirical progress in an environment of uncertainty and partial knowledge: take what is known right now and try to make something of it. It is fair to say that, from a modern materials science perspective, the ancient Romans did not know anywhere near enough about bridge building. But their engineers built great bridges because empirical discovery allows the development of a corpus of knowledge and practical expertise. That practicality can later be fleshed out by the scientists, and in fact tends to help the scientists a great deal. That is what is presently underway in the treatment of aging as a medical condition, and is largely why a growing longevity industry exists at all.
Calling the whole of the longevity industry into question because geroscience is the wrong direction is throwing the baby out with the bathwater.
Inflated expectations: the strange craze for translational research on aging
The emergence of Hevolution and the XPRIZE Healthspan is just the latest development in a remarkable phenomenon: a dramatic upsurge in activity in the private sector aimed at developing treatments for aging, fuelled by a heady optimism that the time is nigh. Other examples that involve massive funding to achieve practical outcomes in applied research on aging include the California Life Company (Calico), into which some 2.5 billion has been invested; and Altos Labs, which in 2022 raised 3 billion from investors.
Here we ask the question: what is the basis for this optimism? The last quarter of a century has seen a concerted effort by scientists to understand the fundamental biological mechanisms of aging, and much ground has been covered. How has this informed the recent upswell in commercial activity? We suggest that the latter is an anomaly arising in part from developments within the aging research field a decade ago that were, in some ways, counterproductive. These include the emergence of the so-called geroscience research agenda.
What seems to have happened is the following. Advances in research on the biology of aging that culminated in the 1990s yielded startling implications. It seemed possible not only to understand the fundamental mechanisms of aging, but also to slow them down. These promising prospects led to the aging field becoming bigger and better, thanks to increased funding and the influx of many good scientists. As a result, standards of research grew more rigorous, including critical reassessments of earlier findings. Such careful research over the past two decades has, regrettably, undermined a number of the reasons for earlier optimism. Disappointingly, caloric restriction in rhesus monkeys proved not to have the same remarkable effects as those seen in rodents. Growth hormone defects that extend lifespan in mice were found not to do so in humans.
With the dwindling likelihood that humans possess the plasticity in aging seen in shorter-lived animals, and the failure of existing theories of aging, how should one further pursue research? Here two possible approaches may be envisaged. On the one hand, scientists could renew their efforts to develop an effective theoretical framework with the capacity to explain diverse phenomena of aging. On the other hand, research could focus on translating existing theoretical claims and experimental observations into therapeutic trials – preclinical or clinical. The pursuit of this strategy in the early 2010s marked the emergence of the geroscience agenda.
In the past, this strategy of prioritizing translational research in the absence of a good understanding of the basic science has sometimes proved successful, aided by brute force and serendipity. There are, however, also numerous instances where such trial-and-error approaches failed, sometimes involving investment of billions. The reader may pick their own examples. Unquestionably, for translational research to yield useful, practical applications, at least some level of scientific understanding is required. At issue is judging when the time is ripe to move from basic to translational research, particularly where large investments of money and effort are involved. The oddest thing about the translational geroscience approach is its combination of pessimism about understanding aging, and optimism about translational research. Arguably, the inverse is more realistic.
Lifespan.io and Peter Diamandis on the Challenges of Funding Development of Therapies to Treat Aging
https://www.fightaging.org/archives/2024/08/lifespan-io-and-peter-diamandis-on-the-challenges-of-funding-development-of-therapies-to-treat-aging/
Some years after first coming to the conclusion that treating aging as a medical condition is possible, a great idea, something that should be supported by vastly more research and development funding than is actually the case, one starts to lose touch with how most people think about aging, medical research, and medicine. Which is to say that it is in the background, not thought about that much at all, and aging is taken for granted. Not a big problem, just the state of things. It is akin to all of those people who don’t think much about cancer medicine until they develop a cancer, and even then treat the state of medical capabilities as set in stone, a fixed state of the world to be guided through by a physician rather than a potentially adjustable, changeable field to learn, engage with, and try to improve on.
Most individuals with the capability to direct large sums of funding into research think this way. Wealth doesn’t grant any particular capacity for vision or interest in aging and longevity. There is also, I think, a tendency in various non-profit and advocacy circles to conceive of billionaires as having a great deal more agency than is in fact the case when it comes to the ability to direct funds to causes. A billionaire is the figurehead of, figuratively, a small country with its various power blocks and interest groups. The billionaire is shaped by that as much as he or she shapes it in return. There is an intrinsic conservatism to very large aggregations of wealth and power; they are usually the last to the table when it comes to supporting novel directions. The exceptions are noteworthy and receive more than their share of media attention, but they are exceptions.
Peter Diamandis: “Stay Healthy, Anti-Aging Tech is Coming”
Billionaires sit on vast resources, but they don’t seem to be ready to massively invest in longevity yet. But it shouldn’t be just about the money. This is literally about life and death.
You’re absolutely right, but that’s just not the way they’re viewing it. You could say that all of us put our money in three different buckets. There’s a bucket for money that will be used to make more money. Another one is for money that will be used for family, enjoyment, vacations, and so on. And the last one is for helping people. Unfortunately, for most people, that last bucket is the smallest by orders of magnitude.
I think it’s not just about philanthropy. It should also be driven by egoistic considerations. Maybe there’s a place for a fourth bucket, where you help humanity, but you also help yourself. After all, today, death is pretty inescapable whether you’re a billionaire or a construction worker. Even more so than, say, climate change.
It seems obvious to me. Why aren’t people acting in their own self-interest? This thing should hit every bucket. I’m going to invest in longevity because it’s going to help me, my family, and humanity, and it will also allow me to feel better, to have a happier life. And it’s also a huge business opportunity, right? The only reason that’s not hitting is that people don’t believe it yet. We have been so indoctrinated about the inevitability of death!
I try to change it, by writing books about this. My mission is to help the public create a longevity mindset, which is based on the realization that the technology to enable us to extend the healthy human lifespan is coming online now, in the decade ahead. And if you believe that in the next ten years, we’re going to significantly extend the human healthspan, and you can have access to it if you’re in good health, then, logically, you’d want to do everything you can to remain in the best health possible. I want people to change the way they think about healthspan and longevity and what’s possible for them. Because your mindset is the most powerful tool that you have. If you believe it, you’re going to change your behavior.
The Brain Accumulates Mitochondrial DNA Inserts into the Nuclear Genome
https://www.fightaging.org/archives/2024/08/the-brain-accumulates-mitochondrial-dna-inserts-into-the-nuclear-genome/
A cell is a bag of molecules moving at incredible velocities, all running into one another countless times every second. Almost anything is possible in this high speed environment, albeit that some outcomes are highly unlikely in any given second. There are a lot of seconds and even more cells, however. Thus it is possible for fragments of mitochondrial DNA to somehow find their way into the cell nucleus and then somehow be incorporated into nuclear DNA. Evolution has made full use of this rare happenstance, as most of the original mitochondrial DNA, the genome of symbiotic bacteria that lived within the first eukaryotic cells, has shifted over evolutionary time: firstly forming viable genes in the nuclear genome, and then secondly the mitochondrial sequences deleted through forms of DNA damage.
Researchers here measure the occurrence of mitochondrial DNA inserts into the nuclear genome in human brain tissue. Interestingly, they find a correlation with mortality. This could be indicative that this sort of mutational damage is producing materially detrimental effects on tissue function; the arguments to be made here are similar to those for the role of somatic mosaicism in degenerative aging. Equally this may be a case in which greater age-related mitochondrial dysfunction produces a greater chance of mitochondrial DNA making its way into the nucleus. It is already known that aging is associated with inflammation driven by innate immune recognition of mislocalized mitochondrial DNA fragments in the cytosol. It seems sensible to hypothesize that more of this means more rare nuclear localization events.
Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts
The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in nonhuman species. Here, we investigated numtogenesis dynamics in humans in 2 ways. First, we quantified Numts in 1,187 postmortem brain and blood samples from different individuals. Compared to circulating immune cells (n = 389), postmitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples, we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex (DLPFC) compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, an increase in the number of brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment (NCI) who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer.
Second, we tested the dynamic transfer of Numts using a repeated-measures whole-genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging. These longitudinal experiments revealed a gradual accumulation of 1 Numt every ~13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven by cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7-fold faster than healthy donors.
Combined, our data documents spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human postmitotic tissues produces functionally relevant human Numts over timescales shorter than previously assumed.
p53 in Aging and Senescence Across Species
https://www.fightaging.org/archives/2024/08/p53-in-aging-and-senescence-across-species/
The traditional view of the p53 tumor suppressor gene is that it is a representative mechanism in the evolved trade-off between suppression of cancer on the one hand and harmful buildup of senescent cells on the other. Specifically p53 is an important part of the machinery that induces cellular senescence in response to potentially cancerous mutational damage. A senescent cell ceases replication and secretes inflammatory signals in order to attract immune cells to destroy it and any other problem cells in the immediate vicinity. Unfortunately immune mediated clearance of senescent cells becomes less effective with advancing age, allowing a build up of a lingering senescent cell population. Their signaling is harmful to tissue structure and function.
So a lesser degree of p53 activity implies a lesser burden of cellular senescence in later life, and thus a slower pace of aging, but also a greater risk of cancer. More aggressive p53 activity impedes cancer, but then leads to greater cellular senescence and a shorter life span. This is an oversimplification of a more complicated picture, however. Once one starts to look into the biochemistry of diverse species, one finds all sorts of different variations on how p53-driven mechanisms relate to aging and cancer. For example, elephants have many copies of p53 and aggressive anti-cancer activity in general, but are nonetheless long-lived mammals. There is a great deal more to consider than just p53 when it comes to understanding the relevance of p53.
Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders
Usually, aging is a gradual process characterized (in humans and mouse models) by molecular biomarkers such as a decrease in leukocyte telomere length, decreased levels of IGF-1, and increased inflammation. Several molecular mechanisms have been purported to regulate aging and determine lifespan – many of which have been linked to p53 tumor suppressor activities. In low or high-stress conditions, p53 binds to several target genes – including those that encode PML, PAI-1, and DEC1 – which then induce cellular senescence. The link between aging and its ability to push cells to senescence is of particular interest to this study. In a senescent state, a damaged cell resists apoptosis and ceases to replicate. An accumulation of these cells triggers the aging process by creating a senescence-associated secretory phenotype (SASP) which creates a chronic inflammatory microenvironment. It has been shown that a programmed clearance of senescent cells delays aging phenotypes.
While p53 consensus sequences for most of these targets have been elucidated, few studies have explored regulatory mechanisms and structural features of p53 that could be implicated in organismal aging. Residual changes in the DNA-binding domain of several orthologs of p53 in Cetaceans have been linked to longevity. This supports findings that p53-mediated cellular senescence could be mediated directly by DNA binding. Additionally, there has been an extension exploration of the role of the mouse MDM2 gene in the aging process of mice. MDM2 is the most well-studied negative inhibitor of p53 tumor suppressive activity; disruption of the MDM2-p53 axis accelerates aging in some mice, suggesting the importance of the MDM2-p53 axis to the aging process.
However, p53’s link to organismal aging may not be easily explainable just by the MDM2-p53 axis. MDM2 has only minor regulatory effects on the levels of p53 in the naked mole rat. And, interestingly, the naked mole rat lives an average of 30 years compared to an average of 2-4 years for most rodents. This is thought to be due in part to a hyperstable p53 – the source of this stability remains largely unknown. In another case, the African elephant despite being predisposed to cancer due to prolonged UV-radiation and large body mass lives comparably long lives and displays a significantly lower frequency of cancer when compared to humans. The unique presence of 20 copies of p53 in their genome is thought to be responsible for this.
This study seeks to elucidate, structurally and mechanistically, p53’s roles in longevity. Through a relative evolutionary scoring (RES) algorithm, we quantify the level of evolutionary change in the residues of p53 across organisms of varying average lifespans in six taxonomic orders. Secondly, we used the PEPPI protein-protein interaction predictor to assess the likelihood of interaction between p53 – or p53-linked proteins – and known senescence-regulating proteins across organisms in the orders Primates and Perciformes. Our RES algorithm found variations in the alignments within and across orders, suggesting that mechanisms of p53-mediated regulation of longevity may vary. PEPPI results suggest that longer-lived species may have evolved to regulate induction and inhibition of cellular senescence better than their shorter-lived counterparts. With experimental verification, these predictions could help elucidate the mechanisms of p53-mediated cellular senescence, ultimately clarifying our understanding of p53’s connection to aging in a multiple-species context.
Towards Progressive Replacement of the Aging Neocortex
https://www.fightaging.org/archives/2024/08/towards-progressive-replacement-of-the-aging-neocortex/
Cancer, stroke, and other injuries to the brain have provided some insight into how the brain can restructure in response to damage. Provided that the damage progresses relatively slowly, as in the case of brain cancers, areas of the brain such as the neocortex can create new functional networks in order to maintain capabilities. When damage is fast, as in stroke, capabilities are lost. A few researchers see this as proof that it should be possible in principle to slowly and incrementally replace aged and damaged brain tissue with youthful tissue, given sufficiently advanced tissue engineering technology.
The focus of Jean Hébert’s scientific work is the neocortex, the outer part of the brain that looks like a pile of extra-thick noodles and which houses most of our senses, reasoning, and memory. The neocortex is “arguably the most important part of who we are as individuals, as well as maybe the most complex structure in the world.” There are two reasons Hébert believes the neocortex could be replaced, albeit only slowly. The first is evidence from rare cases of benign brain tumors, like a man described in the medical literature who developed a growth the size of an orange. Yet because it grew very slowly, the man’s brain was able to adjust, shifting memories elsewhere, and his behavior and speech never seemed to change – even when the tumor was removed. That’s proof, Hébert thinks, that replacing the neocortex little by little could be achieved “without losing the information encoded in it” such as a person’s self-identity.
The second source of hope, he says, is experiments showing that fetal-stage cells can survive, and even function, when transplanted into the brains of adults. For instance, medical tests underway are showing that young neurons can integrate into the brains of people who have epilepsy and stop their seizures. “It was these two things together – the plastic nature of brains and the ability to add new tissue – that, to me, were like, ‘Ah, now there has got to be a way.'”
One challenge ahead is how to manufacture the replacement brain bits, or what Hébert has called “facsimiles” of neocortical tissue. During a visit to his lab Hébert described plans to manually assemble chunks of youthful brain tissue using stem cells. These parts, he says, would not be fully developed, but instead be similar to what’s found in a still-developing fetal brain. That way, upon transplant, they’d be able to finish maturing, integrate into your brain, and be “ready to absorb and learn your information.” To design the youthful bits of neocortex, Hébert has been studying brains of aborted human fetuses 5 to 8 weeks of age. He’s been measuring what cells are present, and in what numbers and locations, to try to guide the manufacture of similar structures in the lab.
Hébert’s ideas appear to have gotten a huge endorsement from the US government. Hébert has proposed a 110 million project to ARPA-H to prove his ideas in monkeys and other animals, and that the government “didn’t blink” at the figure. ARPA-H confirmed this week that it had hired Hébert as a program manager.
Exploring the Details of Thymic Involution
https://www.fightaging.org/archives/2024/08/exploring-the-details-of-thymic-involution/
The thymus is necessary for the production of T cells of the adaptive immune system. Active thymic tissue diminishes with age to be replaced with fat, a process known as involution. This reduces the supply of new T cells and is an important contribution to the aging of the immune system. It may be that a better understanding of the fine details of the atrophy of the thymus with age may lead to new approaches to therapy. At present, the few groups working on rejuvenation of the thymus are largely focused on either delivering cells to the thymus or finding ways to upregulate the well-known regulatory pathway for thymic growth relating to the FOXN1 gene. There may be other ways forward.
The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons.
We applied single-cell and spatial transcriptomics, lineage-tracing, and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1.
Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.
In Search of Stem Cells in Immortal Lower Animals
https://www.fightaging.org/archives/2024/08/in-search-of-stem-cells-in-immortal-lower-animals/
Some lower animals are effectively immortal, in that their risk of mortality doesn’t appear to increase over time. This has been demonstrated for hydra, and some other marine species have an analogous, highly regenerative biology, such as a few jellyfish and the sea anemone species noted here. Notably, none of these animals have a sophisticated nervous system and brain. The evolution of neural tissue that can store complex data appears incompatible with a lack of degenerative aging built on constant, highly proficient regeneration and replacement of all portions of the body as needed.
While humans and most vertebrates can only regenerate parts of certain organs or limbs, other animal groups have far stronger regeneration mechanisms. This ability is made possible by pluripotent or multipotent stem cells, which can form (differentiate) almost all cell types of the body. The sea anemone Nematostella vectensis is also highly regenerative: it can reproduce asexually by budding and also shows no signs of ageing, which makes it an interesting subject for stem cell research. However, researchers have not yet been able to identify any stem cells in these animals.
“By combining single-cell gene expression analyses and transgenesis, we have now been able to identify a large population of cells in the sea anemone that form differentiated cells such as nerve cells and glandular cells and are therefore candidates for multipotent stem cells.”
These potential stem cells express the evolutionarily highly conserved genes nanos and piwi, which enable the development of germ cells in all animals, including humans. By specifically mutating the nanos2 gene using the CRISPR gene scissors, the scientists were also able to prove that the gene is necessary for the formation of germ cells in sea anemones. It has also been shown in other animals that this gene is essential for the production of gametes. This proves that this gene function emerged around 600 million years ago and has been preserved to this day. In future studies, researchers now want to investigate which special properties of the sea anemone’s stem cells are responsible for its potential immortality.
A Look at the Basis for Glycosylation Clocks to Measure Biological Age
https://www.fightaging.org/archives/2024/08/a-look-at-the-basis-for-glycosylation-clocks-to-measure-biological-age/
Immunoglobulins are the molecules making up antibodies. Post-translational modification of immunoglobulin molecules changes their function, and is a complex aspect of this portion of the immune system, altering the character of immune responses. The post-translational modification of glycosylation has been shown to shift in characteristic ways in immunogloblins with age. Analysis of these changes has given rise to the GlycanAge clock for the measurement of biological age. Here, researchers review what is known of these age-related changes and their relevance to specific aspects of immune aging.
Immunoglobulin G (IgG) is an important serum glycoprotein and a major component of antibodies. Glycans on IgG affect the binding of IgG to the Fc receptor or complement C1q, which in turn affects the biological activity and biological function of IgG. Altered glycosylation patterns on IgG emerge as important biomarkers in the aging process and age-related diseases. Key aging-related alterations observed in IgG glycosylation include reductions in galactosylation and sialylation, alongside increases in agalactosylation, and bisecting GlcNAc.
Understanding the role of IgG glycosylation in aging-related diseases offers insights into disease mechanisms and provides opportunities for the development of diagnostic and therapeutic strategies. This review summarizes five aspects of IgG: an overview of IgG, IgG glycosylation, IgG glycosylation with inflammation mediation, IgG glycan changes with normal aging, as well as the relevance of IgG glycan changes to aging-related diseases. This review provides a reference for further investigation of the regulatory mechanisms of IgG glycosylation in aging-related diseases, as well as for evaluating the potential of IgG glycosylation changes as markers of aging and aging-related diseases.
Senescent Cells in Aged Tissues May Use Immune Checkpoints to Prevent Immune Clearance
https://www.fightaging.org/archives/2024/08/senescent-cells-in-aged-tissues-may-use-immune-checkpoints-to-prevent-immune-clearance/
Immune clearance of senescence cells falters with age, becoming less efficient. This allows lingering senescent cells to accumulate, and their disruptive, inflammatory secretions contribute meaningfully to degenerative aging and age-related mortality. Greater knowledge of how exactly the immune system fails in its job may open novel avenues in the development of senolytic therapies to clear senescent cells – look at the work of Deciduous Therapeutics, for example. Here, researchers note that senescent cells appear to make use of immune checkpoints to fend off immune clearance. This area of biochemistry is well explored in connection with cancer immunology, and it may turn out to help in the context of senescent cells.
The accumulation of pro-inflammatory senescent cells within tissues is a common hallmark of the aging process and many age-related diseases. This modification has been called the senescence-associated secretory phenotype (SASP) and observed in cultured cells and in cells isolated from aged tissues. Currently, there is a debate whether the accumulation of senescent cells within tissues should be attributed to increased generation of senescent cells or to a defect in their elimination from aging tissues.
Emerging studies have revealed that senescent cells display an increased expression of several inhibitory immune checkpoint ligands, especially those of the programmed cell death protein-1 (PD-1) ligand-1 (PD-L1) proteins. It is known that the PD-L1 ligands, especially those of cancer cells, target the PD-1 receptor of cytotoxic CD8+ T cells and natural killer (NK) cells disturbing their functions, e.g., evoking a decline in their cytotoxic activity and promoting their exhaustion and even apoptosis. An increase in the level of the PD-L1 protein in senescent cells was able to suppress their immune surveillance and inhibit their elimination by cytotoxic CD8+ T and NK cells. Senescent cells are known to express ligands for several inhibitory immune checkpoint receptors, i.e., PD-1, LILRB4, NKG2A, TIM-3, and SIRPα receptors.
Here, I will briefly describe those pathways and examine whether these inhibitory checkpoints could be involved in the immune evasion of senescent cells with aging and age-related diseases. It seems plausible that an enhanced inhibitory checkpoint signaling can prevent the elimination of senescent cells from tissues and thus promote the aging process.
Amyloid-β Monomer Clearance with Anticalins
https://www.fightaging.org/archives/2024/08/amyloid-%ce%b2-monomer-clearance-with-anticalins/
Researchers here argue that the fine details of how and when amyloid-β is cleared from the brain matters greatly in the treatment of Alzheimer’s disease. To make the point they use a form of antigen-binding protein known as an anticalin, a technology that produces similar outcomes to monoclonal antibodies but with fewer inflammatory side-effects. The researchers target forms of amyloid-β that arise prior to the formation of amyloid plaques, attacking the very earliest stages leading to pathology. It works in a mouse model of Alzheimer’s disease, but it is worth bearing in mind that these models are very artificial and a great deal of what has worked in mice has failed in humans.
Until relatively recently, treatment strategies aiming at the scavenging of amyloid-β (Aβ) by passive immunization with antibodies have largely failed to show a significant deceleration of cognitive decline in clinical studies, in fact raising concerns about the amyloid hypothesis. Similar discouraging observations were made in Alzheimer’s mouse models. There are several possible explanations for the general failure of these approaches, most prominently an inadequate timing of the therapeutic intervention after the brain has already undergone irreparable damage.
Moreover, anti-Aβ treatment at very early stages of development had positive outcomes in mouse models of amyloidosis. Thus, before Aβ plaque formation, the prevention of extracellular Aβ accumulation involving the use of γ-secretase inhibitors can effectively abolish neuronal hyperactivity. This is relevant because a variety of studies in mice and humans have established that neuronal hyperactivity is probably the earliest form of neuronal dysfunction in the diseased brain.
To untangle the conflicting results on the effectivity of Aβ removal obtained from previous mouse studies, we applied here an alternative approach based on the direct intracerebral application of Aβ-binding anticalins (Aβ-anticalins). Anticalins exhibit very high target affinities and, in contrast to antibodies, a low immunogenic potential. We demonstrate that an Aβ-anticalin can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of amyloidosis. Our results suggest that the sole targeting of Aβ monomers is sufficient for the hyperactivity-suppressing effect of the Aβ-anticalin at early disease stages.
The Relationship Between Physical Fitness and Biological Age
https://www.fightaging.org/archives/2024/08/the-relationship-between-physical-fitness-and-biological-age/
Early epigenetic clocks were insensitive to physical fitness, which didn’t make much sense given the evident relationship between physical fitness and mortality risk in later life. Later, better epigenetic clocks have shown that physically fit individuals tend towards a lower biological age. To date, near all pharmacological interventions shown to adjust metabolism in ways that modestly slow aging, and for which human data exists, have failed to improve upon the effects of exercise. Exercise remains the low bar to beat for the longevity industry.
In this context, exercise is a powerful “geroprotector” that is well-recognized to extend the human health span. However, the relationship between physical fitness and biological age, based on the DNA methylation (DNAm) aging clock, is poorly understood. Most previous studies investigated the relationship between physical activity and DNAm aging clocks based on questionnaires and accelerometers using a molecular epidemiological approach. Theoretically, physical activity and fitness differ, with physical fitness considered the result of exercise, which is planned and regular physical activity. Considering that various health outcomes can be strongly associated with fitness, especially cardiorespiratory fitness (CRF), rather than with physical activity, CRF can be a stronger geroprotector than physical activity. Therefore, in the field of geroscience, it can be valuable to investigate the relationship between CRF and the DNAm aging clock and determine fitness reference values for delaying aging.
We attempted to determine the relationship between CRF and various lifestyle-related factors associated with biological aging based on DNAm aging clocks. We found that CRF was negatively related to epigenetic age acceleration, even after adjusting for confounders (chronological age, smoking, and alcohol consumption), and that maintenance of CRF above a reference value (i.e., 22.7 mL/kg/min) was associated with lower age acceleration. Collectively, these findings suggest that although the relative contribution of CRF to biological aging is relatively low when compared with lifestyle-related variables, such as smoking, the maintenance of CRF is associated with delayed biological aging in older males.
The central concern of exercise scientists is determining the causal relationship between CRF and biological aging. Several cross-sectional studies, including ours, have only demonstrated the relationship between physical activity, physical fitness, and biological aging; however, the causal relationship between them remains elusive. To prove a causal relationship, it is necessary to conduct longitudinal studies that track age-related changes in both CRF and DNAm aging clocks, as well as endurance exercise training intervention studies. In mouse studies, late-life exercise training could delay epigenetic aging of skeletal muscle. In humans, exercise training reportedly leads to epigenetic patterns toward a younger profile. Another study has reported that the number of subjects with higher baseline levels of epigenetic age acceleration decreased after exercise training
PGK1 is Rate-Limiting for ATP Production in Neurons
https://www.fightaging.org/archives/2024/08/pgk1-is-rate-limiting-for-atp-production-in-neurons/
Mitochondria must produce the chemical energy store molecule ATP in order for cells to function. The neurons lost in Parkinson’s disease are particularly vulnerable on this front, and the state of their mitochondrial function is important in determining how vulnerable a patient is to the underlying protein aggregation mechanisms that drive cell dysfunction and death. Researchers here discuss a protein that is rate-limiting in the production of ATP via glycolysis in neurons, and show that even slightly upregulating its expression can be protective. One might think that this is an enhancement that could be generally beneficial to brain cells and brain function, given a safe means of upregulation, as the brain is usually running at the very edge of metabolic capacity even in youth.
The brain is a metabolically vulnerable organ suffering acute functional decline when fuel delivery is compromised. We previously showed that central nervous system nerve terminals rely on efficient activity-dependent up-regulation of ATP synthesis to sustain function and undergo abrupt synaptic collapse when this process fails. Reduced fuel delivery to the brain is correlated with aging and is an early predictor of eventual neurological dysfunction, suggesting that as fuel delivery becomes compromised, synaptic function becomes increasingly vulnerable to genetic metabolic lesions. Parkinson’s disease (PD) has long-been thought to be, in part, driven by metabolic vulnerability of dopamine (DA) neurons of the substantia nigra pars compacta (SNc) as two of the earliest identified genetic drivers of PD, PARK2 and PARK6, when mutated, compromise the integrity of mitochondria.
Several recent discoveries point to a critical but unexpected outsized role of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) in protecting neurons against neurological impairment. PGK1, the first ATP-producing enzyme in glycolysis, catalyzes the sixth step in this 10-step enzymatic cascade. A chemical screen of a subset of FDA-approved drugs capable of suppressing cell death identified terazosin (TZ) as a weak (~4%) off-target activator of PGK1. TZ was subsequently shown to confer significant protection in numerous models of PD (mouse, rat, Drosophila, and human induced pluripotent stem cells), implying that contrary to expectations, PGK1 activity is a critical modulator of glycolytic throughput. Clinical use of TZ for treatment of benign prostate hyperplasia provided data for a retrospective analysis, which showed that prolonged use of TZ reduced the risk of developing PD by up to ~37% compared to tamsulosin, whose chemical structure differs significantly from TZ but has the same molecular target.
These data all predict that PGK1 activity is a crucial leverage point in neuronal bioenergetic control and that bioenergetic deficits, in turn, underpin many forms of PD. Here, we demonstrate that PGK1 is the rate-limiting enzyme in axonal glycolysis and that modest changes in PGK1 activity accelerate neuronal ATP production kinetics capable of reversing the synaptic deficit driven by the PARK20 mutation. We identified PARK7/DJ-1, the PD-associated molecular chaperone, as a necessary gene for PGK1 to up-regulate ATP production as loss of PARK7/DJ-1 itself led to deficits in neuronal glycolysis that impaired the ability of PGK1 up-regulation to provide protection. We showed that increasing PGK1 abundance in vivo offered strong protection against striatal DA axon dysfunction. These data strongly support the idea that PGK1 serves as a critical lever arm in controlling axonal bioenergetics.
Immunomodulatory Protein Derived from Parasites Enhances Regeneration in Mice
https://www.fightaging.org/archives/2024/08/immunomodulatory-protein-derived-from-parasites-enhances-regeneration-in-mice/
Researchers here exploit an interesting source of immunomodulatory proteins, parasitic worms that live in the mammalian intestine. The protein of interest inhibits TGF-β signaling, which in turn adjusts the innate immune cells known as macrophages into a more pro-regenerative state at a site of injury. This enables regeneration of injuries with a lesser degree of scarring. In skin, hair follicles regrow rather than being replaced by scar tissue, for example. Most of the approaches demonstrated to enhance regeneration in animal models should in principle have some application to the problem of reduced capacity for healing in older people, so it is worth keeping an eye on this part of the field of regenerative medicine.
The balance between scarring and successful tissue regeneration is strongly influenced by immune cells recruited to the wound site, and many researchers are interested in finding ways to boost the activity of immune cell types that promote regeneration while inhibiting the activity of immune cells that promote tissue scarring. Recent studies have suggested that molecules secreted by parasitic worms might modulate the host’s immune system in ways that promote tissue regeneration.
In a new study, researchers investigated a protein called TGF-β mimic (TGM) that is produced by Heligmosomoides polygyrus, a parasitic roundworm that lives in the intestines of mice and other rodents. The researchers found that daily topical applications of TGM accelerated the closure of skin wounds in mice. Moreover, TGM treatment reduced the formation of scar tissue while enhancing skin regeneration. For example, unlike untreated animals, TGM-treated mice were able to form new hair follicles within the wounded region of the skin.
The researchers determined that TGM works by binding to a signaling protein, called the TGF-β receptor, that is found on the surface of many cell types in mice and humans, including immune cells. TGM treatment appears to stimulate the recruitment of immune cells known as macrophages into wounds and reprograms them to promote tissue regeneration.
Differences Between Mice and Humans in the Assessment of Biological Age
https://www.fightaging.org/archives/2024/08/differences-between-mice-and-humans-in-the-assessment-of-biological-age/
Most of the present forms of assessment of biological age are based on immune cell characteristics in a blood sample. In this paper, researchers look at some of the differences in the biology of mice versus humans that may be relevant to the way in which we should think about animal data versus human data and the utility of various aging clocks. How much can one infer potential utility in humans based on data obtained from mice, and how does that vary by approach to biological age assessment?
Aging significantly impacts the hematopoietic system, reducing its regenerative capacity and ability to restore homeostasis after stress. Mouse models have been invaluable in studying this process due to their shorter lifespan and the ability to explore genetic, treatment, and environmental influences on aging. However, not all aspects of aging are mirrored between species. This review compares three key aging biomarkers in the hematopoietic systems of mice and humans: myeloid bias, telomere attrition, and epigenetic clocks.
Myeloid bias, marked by an increased fraction of myeloid cells and decreased lymphoid cells, is a significant aging marker in mice but is scarcely observed in humans after childhood. Conversely, telomere length is a robust aging biomarker in humans, whereas mice exhibit significantly different telomere dynamics, making telomere length less reliable in the murine system. Epigenetic clocks, based on DNA methylation changes at specific genomic regions, provide precise estimates of chronological age in both mice and humans. Notably, age-associated regions in mice and humans occur at homologous genomic locations. Epigenetic clocks, depending on the epigenetic signatures used, also capture aspects of biological aging, offering powerful tools to assess genetic and environmental impacts on aging.
Taken together, not all blood aging biomarkers are transferable between mice and humans. When using murine models to extrapolate human aging, it may be advantageous to focus on aging phenomena observed in both species. In conclusion, while mouse models offer significant insights, selecting appropriate biomarkers is crucial for translating findings to human aging.
