Be Extraordinary or Be Dead

Ordinary people don't pay much attention to the science of aging. Ordinary people don't keep an eye on the longevity industry or read scientific papers or donate funds to non-profits supporting important research. Ordinary people don't carefully and rationally self-experiment with plausible age-slowing interventions while measuring outcomes. Ordinary people are not signed up for cryopreservation. Ordinary people are not trying to gain access to new medical therapies a decade in advance of approval by regulators, or after approval but well before widespread availability. One could say much the same for ordinary high net worth individuals, by the way. Wealth is no escape from the median.

Which is all fine. Life is what you make of it, an instant of time that is all yours, come and gone in a flash before the yawning abyss of a billion years of a future empty of your present self. There is no meaning to this life beyond the meaning that you ascribe to this life. It is a narrow and winding path, a balancing act between nihilism on the one side and solipsism on the other. Every ordinary person that you pass in the street is their own snowflake of personal choices in ways that you cannot see, whether you judge them for it or not.

Like gravity at the cliff edge, the biology of aging is a force of nature that cares nothing for our opinions on these matters. It runs as it will, and there will come a time when you, and I, and every present adult that you know well will be faced with the consequences of past choices. Given the present state of aging research, and paucity of viable interventions that may slow or reverse aspects of aging, we will all have the one important choice. Every one of us will either have chosen to be extraordinary, to have learned about aging research, supported progress, and sought out therapies well in advance of widespread adoption, or chosen to be dead, accepting the mortality that attends untreated aging.

The processes of degenerative aging and consequent mortality will not wait on indecision. They will not wait for the regulators to slowly approve, or the scientists to slowly innovate, or the entrepreneurs to slowly meander their way towards practical therapies. The hammer will fall, and bodies will fail and die absent the means to treat aging.

In the matter of treating aging as a medical condition, to be extraordinary is to support research that will bear fruit in twenty to thirty years, whether as a patient advocate, funder of academic projects, or by starting a company to shepherd projects to the clinic. To be extraordinary is to read around the subject and try out the most plausible (and plausibly safe) approaches. To be extraordinary is to go to conferences, meet people, learn that the Intervene Immune trials for thymus regrowth are running, and arrange participation. Or the same for tests of Khavinson peptides, or learning how to source and use senolytics, or any number of other approaches that seem more rather than less likely to pay off. To be extraordinary is to have an agreement with a cryonics provider and a plan to ensure that the arrangement works out. To be extraordinary is to take better care of your health in the simple, effective ways that most people omit in this day and age. So few individuals are undertaking these initiatives in any rigorous way, and yet it doesn't take more time or will or effort than any significant hobby.

Be extraordinary or be dead. That choice lies ahead.

A Popular Science View of the Road to Partial Reprogramming Therapies

Reprogramming via expression of the Yamanaka factors slowly transforms somatic cells from tissues of any age into induced pluripotent stem cells that are essentially identical to embryonic stem cells. Along the way, aged epigenetic patterns are reset to a youthful configuration, and age-related decline of mitochondrial function is reversed. This approach recapitulates the cellular rejuvenation that takes place in early embryonic development.

Interestingly, temporarily exposing old animals to Yamanaka factors produces improved health and far less cancer than one might expect. It appears that it may be possible to build therapies for aging based on partial reprogramming, meaning exposing cells to expression of the reprogramming factors for long enough to obtain epigenetic rejuvenation, but not so long as to create pluripotent cells that can go on to generate cancer. The animal data is promising, but it may still turn out to be challenging to establish that point of balance sufficiently well to convince regulators to approve treatments.

An aging research initiative called Altos Labs recently launched with $3 billion in initial financing from backers. This is the latest in a recent surge of investment in ventures seeking to build anti-aging interventions on the back of basic research into epigenetic reprogramming. In December, NewLimit was founded, an aging-focused biotech backed by an initial $105 million investment.

The discovery of the 'Yamanaka factors' - four transcription factors (Oct3/4, Sox2, c-Myc, and Klf4) that can reprogram a differentiated somatic cell into a pluripotent embryonic-like state - transformed stem cell research by providing a new source of embryonic stem cell (ESC)-like cells, induced pluripotent stem cells (iPSCs), that do not require human embryos for their derivation. But in recent years, Yamanaka factors have also become the focus for another burgeoning area: aging research.

So-called partial reprogramming consists in applying Yamanaka factors to cells for long enough to roll back cellular aging and repair tissues but without returning to pluripotency. Several groups have shown that partial reprogramming can dramatically reverse age-related phenotypes in the eye, muscle, and other tissues in cultured mammalian cells and even rodent models by countering epigenetic changes associated with aging. These results have spurred interest in translating insights from animal models into anti-aging interventions.

Even though Life Biosciences and several other startups are investigating Yamanaka factors with a view to reversing human aging, the biology of rejuvenation by reprogramming remains enigmatic and opaque, at best. "These first papers make some astonishing observations. But much more research is needed to dig into the molecular and mechanistic processes that are occurring." Given that fully reprogrammed iPSCs readily form tumors known as teratomas, scientists must determine whether the cellular clock can be wound back safely in humans - which means the race to the clinic will likely be a marathon rather than a sprint.


Towards Clinical Trials for ISRIB

ISRIB has for some years been under investigation as a way to reduce the impact of neurodegeneration and improve cognitive function. It is one of a number of small molecule approaches to upregulate forms of cellular housekeeping, the unfolded protein response in this case. More cellular maintenance in principle means a lower burden of molecular damage and cellular dysfunction at any given time. Since most of these maintenance processes appear to decline in efficacy with age, improvement is a compensatory strategy that might help. In many cases exercise produces more impressive effects than the present state of the art in pharmacology, however. We shall see how ISRIB does in humans, but the mouse data is interesting.

ISRIB has restored memory formation in mice months after traumatic brain injuries and shown potential in treating neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS). It also seems to reduce age-related cognitive decline. Researchers believe that the reason the molecule can do so much is that it plays an essential role in how the brain handles stress from physical injuries or neurological diseases. Under siege from such problems, the brain, in essence, shuts down cognitive functions like memory formation to protect itself. The new molecule reverses that.

Will ISRIB work to reverse cognitive decline in people? We still don't know. So far most of the work has been done in mice or human cells in a petri dish. But we will soon know more: in 2015 the molecule was licensed by Calico Labs, the Silicon Valley biotech established by the founders of Google to find drugs based on the biology of aging. It aims to transform the molecule into a treatment for a wide array of disorders, including ALS and Parkinson's disease, as well as the damage from traumatic brain injury. In 2021, Calico announced that human safety trials had begun on the first drug candidate for neurodegenerative diseases it had developed based on ISRIB, and that a study in ALS patients was slated to begin later in the year.


A Popular Science Overview of the State of Development for Epigenetic Clocks

The development of rejuvenation therapies is haphazard and inefficient in part because measuring rejuvenation is costly, uncertain, and slow. On the one hand, rigorous and convincing data is needed to persuade conservative, risk-averse regulators and sources of funding to support work on rejuvenation at all. Further, cost-effective early guidance on whether one approach is better or worse than another is needed in to order to avoid a great deal of effort directed towards programs that cannot produce sizable outcomes for health.

With this in mind, the research community is in search of a way to rapidly assess biological age before and after potential therapies. Epigenetic clocks are one possible path towards this capability, but as today's popular science article notes, there are sizable hurdles yet to overcome.

It is now straightforward to generate clocks that reflect age and disease risk from near any sizable set of biological data. Many characteristic changes take place with age in the epigenome, proteome, transcriptome, and so forth. Modern machine learning makes it practical to identify such changes in large datasets. The problem is that researchers don't yet know how these changes connect to the underlying processes of aging. Thus no-one knows whether any given clock will accurately reflect the results of adjusting just one or a few of those processes.

So it is simple enough to run clocks on blood samples and produce numbers - but can those numbers be trusted? At the moment, no. Clocks must be calibrated against any potential therapy they are to be used with, via life span studies and other lengthy and costly exercises. That defeats the point of the exercise, to find a faster way forward. The alternative is a great deal more work aimed at understanding exactly how clocks as a category respond to mechanisms of aging.

Turning back time with epigenetic clocks

Biological age is an important concept, albeit a slippery one. Everyone's physical and mental functioning gradually declines from early adulthood onwards, but this occurs at different rates in different people. A technique for measuring biological age detects a signal that is a better guide to a person's functional capacity than their actual, chronological age. As more and more scientists seek to slow, halt or rewind ageing, such methods will be needed to assess whether the new manipulations achieve these goals.

Epigenetic clocks use algorithms to calculate biological age on the basis of a read-out of the extent to which dozens or even hundreds of sites across an individual's genome are bound by methyl groups - a form of epigenetic modification. In 2019, a small study raised the tantalizing prospect that ageing could be reversed. Scientists gave 9 men aged 51 to 65 a growth hormone and two diabetes medications for a year. The drugs seemed to rejuvenate the men's thymus glands and immune function. They also shaved 2.5 years off the men's biological age, as measured by epigenetic clocks.

The study is one of many, in humans and in animals, that seek ways to reduce epigenetic clock scores - and thereby develop new anti-ageing interventions. But some experts are concerned by the unknowns that still surround this technology. "It's become a sort of dogma in the field - and in the popular perception - that these things are really measuring biological ageing. We really need to understand how these things are working. That's the weakness of these biomarkers. They come out of a machine-learning algorithm. They work beautifully in a mathematical sense, but biologists want more."

The US Food and Drug Administration does not currently recognize epigenetic clock scores as surrogate end points for clinical trials. It wants their mechanistic basis to be better defined. And it wants an answer to the crucial question of whether a short-term decrease in someone's epigenetic clock score definitively lowers their chances of developing age-related ill health.

The Relationship Between Immunosenescence and Inflammaging

Immunosenescence is the age-related incapacity of the immune system, while inflammaging is the age-related overactivity of the immune system, overreacting to signals of damage in the body. Both are disruptive to tissue function, health, and odds of survival in later life. They are flip sides of the same coin, labels for emergent properties of the combined interactions of many forms of damage and dysfunction that accumulate with age. The decline of the immune system is clearly important in the onset and progression of many age-related conditions; more resources should be devoted to approaches capable of immune rejuvenation, such as thymic regrowth, restoration of hematopoietic stem cell populations, and the like.

The relationship between immunosenescence and inflammageing is complex, involving the interplay between innate and adaptive arms of the immune system, together with senescent cells from non-immune system lineages, in a potentially vicious cycle. Inflammageing promotes senescence and impedes adaptive immune responses, while this impairment may lead to a greater mobilisation of innate immune cells, thereby favouring inflammageing. With the ageing of the immune system, immunosurveillance becomes less efficient, leading to failure to remove senescent cells. These in turn contribute locally and systemically to inflammation. The evidence discussed above demonstrates an overall imbalance in inflammatory processes, tilting progressively towards increasing inflammation with age, with failure of anti-inflammatory molecules to counteract this. The important interconnections between inflammation, immunosenescence, frailty, and age-related disease have been highlighted further by the development of an accurate ageing clock (iAge) based on inflammatory signatures.

The need to improve immune health and resistance to infectious diseases in older adults has been brought into sharp focus by the COVID-19 pandemic. Herein, we have outlined several strategies to improve elderly immune function and decrease inflammation. Of these, spermidine treatment, mTOR inhibition, and the selective removal of senescent cells using senolytics are most strongly supported by model organism studies and human clinical trial data, with significant scope for immune benefit even against severe infections, such as that caused by SARS-CoV-2. It is possible that combinations of these therapies may be needed to address immunosenescence and inflammageing in the context of an ageing body burdened with accumulated senescent cells.

We recommend that clinical trials of drugs for age-related diseases routinely include analysis of inflammatory mediators in order to determine whether the treatment has the added benefit of ameliorating inflammageing. We conclude that it is essential to investigate a diverse set of inflammation-related molecules to properly analyse the development of chronic inflammation with ageing; new proteomics platforms that permit simultaneous measurement of thousands of factors from very small samples should greatly facilitate such analysis and enable personalised interventions to reduce inflammation and support healthy immune function even in old age.


Short In Vivo Reprogramming Treatment Reverses Age-Related Omics Changes in Mice

Researchers here demonstrate that, in mice, many biological markers of aging (in the epigenome, transcriptome, and metabolome) are made more youthful by a short in vivo exposure to the Yamanaka factors capable of reprogramming cells into induced pluripotent stem cells. That process also resets epigenetic marks on the genome to a youthful configuration, improving mitochondrial function, among other benefits. In this case, the goal of a short treatment is to minimize any possible cell conversion, keeping the reprogramming exposure short enough to only change epigenetic markers, gene expression, and cell behavior to be more youthful. The primary challenge in bringing this class of therapy to the clinic will be the long-term safety questions, how to assess (and then minimize) the risk of cancer via unwanted pluripotency of cells, when the consequences of that risk might take years to become visible in humans.

The expression of the pluripotency factors OCT4, SOX2, KLF4 and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, cycles of brief OSKM expression do not change cell identity but can reverse markers of aging in cells and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome and metabolome in naturally aged mice subject to a single period of transient OSKM expression.

We used the reprogrammable mice known as i4F-B which carries a ubiquitous doxycycline-inducible OSKM transgene, abbreviated as i4F. Mice of both sexes were used, and of different ages; young (females, 13 weeks), old (females, 55 weeks) and very old (males and females, 100 weeks). Doxycycline was administered in the drinking water for a period of 7 days. Mice were sacrificed two or four weeks after doxycycline removal.

We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic and metabolomic changes towards a younger configuration in multiple tissues and in the serum.


Clearing Senescent Cells from the Neural Stem Cell Niche Rapidly Improves Neurogenesis in Old Mice

Neurogenesis is the generation of new neurons in the brain, and their integration into existing neural circuits. It is essential to learning and recovery from injury. Neurogenesis is most studied in the hippocampus, connected to memory, and in mice. In humans the debate continues over the degree to which neurogenesis takes place in adult life, and where in the brain it does take place, but the pendulum leans towards this being a significant process over much of the life span. Importantly, neurogenesis appears to decline with age, while increasing neurogenesis produces benefits to cognitive function.

This context is why today's open research materials make for an interesting expansion of the known benefits of senolytic drugs. Senolytic therapies are those capable of selectively destroying senescent cells. Cells become senescent throughout life, usually upon reaching the Hayflick limit to cell replication, but also as a result of damage and stress. Senescent cells enter a state in which they cease replication and actively secrete pro-growth, pro-inflammation signals. The immune system clears senescent cells efficiently in youth, but with age and declining immune function these cells grow in number. Their secretions cause considerable harm to surrounding cell and tissue function. Removing these lingering senescent cells produces rapid rejuvenation in many tissue types. As today's paper illustrates, that includes a reversal of declining neurogenesis.

Old neurons can block neurogenesis in mice

In the new study, researchers tested the idea that increased senescence within the neural stem cell niche negatively impacts adult neurogenesis, focusing on the middle-aged mouse brain. They observed an aging-dependent accumulation of senescent cells, largely senescent stem cells, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of the senescent cells via a drug called ABT-263 caused a rapid increase in normal stem cell proliferation and neurogenesis, and genetic ablation of senescent cells similarly activated hippocampal stem cells.

This burst of neurogenesis had long-term effects in middle-aged mice. One month after treatment with ABT-263, adult-born hippocampal neurons increased and hippocampus-dependent spatial memory was enhanced. "The surprise for us is that only one injection of the drug was sufficient to mobilize the normal stem cells in the hippocampus, and it did so after only 5 days. The newly awakened stem cells continued to function well for the next 30 days."

These results support the idea that the aging-dependent accumulation of senescent cells, including senescent stem cells in the hippocampal niche, negatively affects normal stem cell function and adult neurogenesis, contributing to an aging-related decline in hippocampus-dependent cognition. Moreover, the results provide a potential explanation for the previously observed age-related decreases in hippocampal stem cells and neurogenesis. A large proportion of stem cells becomes senescent, making them unavailable to generate new neurons, and these senescent stem cells likely adversely affect neurogenesis from their non-senescent neighbors.

Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche

Senescent cells are responsible, in part, for tissue decline during aging. Here, we focused on central nervous system (CNS) neural precursor cells (NPCs) to ask if this is because senescent cells in stem cell niches impair precursor-mediated tissue maintenance. We demonstrate an aging-dependent accumulation of senescent cells, largely senescent NPCs, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of senescent cells via acute systemic administration of the senolytic drug ABT-263 (Navitoclax) caused a rapid increase in NPC proliferation and neurogenesis. Genetic ablation of senescent cells similarly activated hippocampal NPCs.

This acute burst of neurogenesis had long-term effects in middle-aged mice. One month post-ABT-263, adult-born hippocampal neuron numbers increased and hippocampus-dependent spatial memory was enhanced. These data support a model where senescent niche cells negatively influence neighboring non-senescent NPCs during aging, and ablation of these senescent cells partially restores neurogenesis and hippocampus-dependent cognition.

Assessing the Ability of Urolithin A Supplementation to Improve Human Health via Increased Mitophagy

Mitophagy is the name given to cellular quality control mechanisms responsible for destroying worn and damaged mitochondria. Existing mitochondrial divide to make up the losses. Mitophagy is critical to mitochondrial function, but it declines in effectiveness with advancing age. A number of dietary supplements are thought to upregulate mitophagy in older individuals, thereby improving mitochondrial function and overall health. Urolithin A is one of them, various vitamin B3 derivatives such as nicotinamide riboside another, as well as mitoQ, SkQ1, and other mitochondrially targeted antioxidants. The mechanisms are varied, as a number of different changes with age are implicated in failing mitophagy. There is some positive evidence for health benefits in humans, but overall the data to date is not good enough for real excitement. That is also the case for the results here. Exercise tends to outperform the supplements where the direct comparison has been made.

Urolithin A is a byproduct of a person's gut bacteria and a diet comprising polyphenols found in pomegranates, berries, and nuts. Supplemental urolithin A has been shown in animal tests and molecular studies of humans to stimulate mitophagy. Researchers studied a small cohort of people over age 65 who were randomized to receive a placebo or a daily supplement of 1,000 mg urolithin A for four months. Each of the 66 subjects was confirmed at the outset to have average or subpar capacity to produce adenosine triphosphate (ATP), which mitochondria produce to help cells perform myriad functions. The investigators hypothesized that, if the urolithin A supplement indeed boosted mitophagy, the test cohort would experience improved muscle function and greater ATP output.

Across both cohorts, two comparisons of muscle function were found to support the thesis, but two others did not. Two measures of muscle endurance were improved in the supplemented group compared to the placebo group. Endurance was measured with exercises involving the hand and leg. Researchers measured the increase in the number of muscle contractions until fatigue between a baseline test and the final test four months later. Measures of distance covered during a six-minute walk improved markedly between tests at baseline and four months in both the supplement and placebo groups. However, researchers saw no significant effect of the supplement compared with the placebo. Measures (via magnetic resonance spectroscopy) of improvement of maximal ATP production did not change significantly between baseline and four months in either group.

Plasma samples also were collected from study participants at the outset, at two months and four months. The purpose was to assess supplement's potential effect on urolithin A bioavailability and on biomarkers of mitochondrial health and inflammation. In the test cohort, Urolithin A was associated with a significant reduction in several acylcarnitines and ceramides implicated for their roles in metabolic disorders involving mitochondria. "These changes suggest that the treatment affects the metabolic condition of people. Even though it didn't affect the maximum ATP production, it improved test subjects' general metabolism."


Depletion of Arginine as a Calorie Restriction Mimetic Strategy

Researchers have shown that depleting the amino acid arginine produces some of the effects of calorie restriction, including loss of fat tissue and upregulation of autophagy. In this open access paper, researchers use a few different approaches to this end to illustrate that this may be a viable strategy for improved health. As is the case for all calorie restriction mimetics, it is worth recalling that (a) effects on long-term health and life span in short-lived species are larger than those in long-lived species, and (b) the actual practice of calorie restriction will usually be more effective than an intervention that targets only some of the many mechanisms involved.

Intermittent fasting and caloric restriction (IF and CR) are effective therapies against obesity and its complications, including non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, in mice and in humans. However, intensive lifestyle modifications are rarely sustainable in real-world settings. We previously found that the hepatocyte response to glucose deprivation is sufficient to mimic several key therapeutic effects of generalized IF and CR on hepatic steatosis, hepatic inflammation, and insulin resistance, in part by inducing hepatocyte autophagic flux and secretion of the anti-diabetic hepatokine, FGF. We thus set out here to leverage this pathway against metabolic disease. Clinically, this approach is of particular interest, because hepatocyte glucose transport and its downstream pathways are amenable to pharmacological therapy.

We previously identified the arginine ureahydrolase, arginase 2 (ARG2), as a hepatocyte glucose withdrawal-induced factor. Induction of ARG2 is sufficient to exert part of the therapeutic metabolic sequelae of caloric restriction. Subsequent data further demonstrated that arginase 1 and arginase 2 polymorphisms determine circulating arginine levels in arginine-supplemented and unsupplemented dietary contexts. Together, the data initiated the hypothesis that augmenting arginine catabolism can modulate host arginine status - and thereby therapeutically direct energy metabolism.

Here, we demonstrate that conferred arginine iminohydrolysis by the bacterial virulence factor and arginine deiminase, arcA, promotes mammalian energy expenditure and insulin sensitivity and reverses dyslipidemia, hepatic steatosis, and inflammation in obese mice. Extending this, pharmacological arginine catabolism via pegylated arginine deiminase (ADI-PEG 20) recapitulates these metabolic effects in dietary and genetically obese models. These effects require hepatic and whole-body expression of the autophagy complex protein BECN1 and hepatocyte-specific FGF21 secretion. The data thus reveal an unexpected therapeutic utility for arginine catabolism in modulating energy metabolism by activating systemic autophagy, which is now exploitable through readily available pharmacotherapy.


Methionine Restriction Improves the Gut Microbiome

A reduced calorie intake improves health via numerous mechanisms, of which upregulation of the cellular maintenance processes of autophagy is likely the most important. Restricting the intake of selected essential amino acids, particularly methionine, has similar effects, as detection of essential amino acids appears to be the primary way by which cells perform nutrient sensing. Most research to date has focused on the effects of reduced calorie intake on the cells and organs of the body. What about the gut microbiome, however, in light of the new research of recent years indicating its importance in health?

We might ask: to what degree are the long-term benefits of calorie restriction, intermittent fasting, and protein restriction (such as methionine restriction) driven by changes in the gut microbiome? Thus, what are our expectations for the benefits resulting from engineering a better gut microbiome? How interested should we be in approaches such as fecal microbiota transplantation and flagellin immunization that can rejuvenate the aged gut microbiome? These are interesting questions, still in the early stages of exploration in the research community.

Methionine Restriction Improves Gut Barrier Function by Reshaping Diurnal Rhythms of Inflammation-Related Microbes in Aged Mice

Age-related gut barrier dysfunction and dysbiosis of the gut microbiome play crucial roles in human aging. Dietary methionine restriction (MR) has been reported to extend lifespan and reduce the inflammatory response; however, its protective effects on age-related gut barrier dysfunction remain unclear. Accordingly, we focus on the effects of MR on inflammation and gut function.

We found a 3-month methionine-restriction reduced inflammatory factors in the serum of aged mice. Moreover, MR reduced gut permeability in aged mice and increased the levels of the tight junction proteins mRNAs, including those of occludin, claudin-1, and zona occludens-1. MR significantly reduced bacterial endotoxin lipopolysaccharide concentration in aged mice serum.

By using 16s rRNA sequencing to analyze microbiome diurnal rhythmicity over 24 hour, we found MR moderately recovered the cyclical fluctuations of the gut microbiome which was disrupted in aged mice, leading to time-specific enhancement of the abundance of short-chain fatty acid-producing and lifespan-promoting microbes. Moreover, MR dampened the oscillation of inflammation-related TM7-3 and Staphylococcaceae.

In conclusion, the effects of MR on the gut barrier were likely related to alleviation of the oscillations of inflammation-related microbes. MR can enable nutritional intervention against age-related gut barrier dysfunction.

Digging Deeper into Ribosomal Dysfunction in Aging

A ribosome performs the translation portion of the process of gene expression, assembling protein molecules from amino acid building blocks according to the blueprint provided by messenger RNA molecules. The more efficiently a ribosome operates, the better a cell functions. Like all cellular components, the ribosome is negatively impacted by age, leading to a greater rate of errors in protein manufacture. The causes of this decline are not well understood, at least when it comes to drawing a clear line of causation back to the root causes of aging. It is perhaps noteworthy that long-lived naked mole rats have evolved unusually efficient ribosomes - perhaps an indication of their importance.

When folded correctly, proteins carry out their functions and remain soluble in the environment of the cell. Misfolded proteins, by contrast, cannot function properly and tend to stick to each other and other proteins, clogging up cellular processes and generating toxic aggregates. Protein aggregation has been specifically implicated in a wide variety of aging-linked diseases, including Alzheimer's, Parkinson's, frontotemporal dementia, Huntington's disease, and ALS (amyotrophic lateral sclerosis).

To guard against the continual production of misfolded proteins, cells have dedicated "quality control" machinery for fixing or degrading misfolded proteins. Previous research has shown that shortcomings in these processes can lead to aggregation. This research is the first to show the folding defect during ageing starts early in the journey of a protein, when it is made by the ribosome. Because ribosomes are constantly producing large amounts of proteins, these defects cause a subsequent snowball of disfunction.

To start, the researchers used a technique called ribosome profiling, which allowed them to see exactly how ribosomes are moving on the messenger RNA during the act of translation. Amassing data from all the genes translated in young and aged Caenorhabditis elegans roundworms and yeast, the researchers noticed that in older cells ribosomes periodically moved more slowly and were more likely to stall and bump into each other. As one might expect, the researchers saw that decreases in proper ribosome performance aligned with increases in the aging-dependent aggregation of misfolded proteins. One important insight was that the increase in stalling and misfolding overwhelmed the cell's cleaning-up-and-clearing-out quality control failsafes.

In follow-up experiments in worms, the researchers found that even if the overall fraction of newly made proteins with altered translation during aging is low (~10%), this small effect can still be enough to overwhelm the quality control system and trigger significant aggregation that can disrupt many different cellular components or processes. "Every cell normally makes millions of these newly translated proteins. So very slight changes in the efficiency of folding with age will escalate in a vicious cycle where defects in translation lead to an overload of the system, which in turn leads to increased protein aggregates with age that are themselves also toxic."


A Biomarker of Aging Based on Retinal Images

Researchers here discuss analysis of images of the retina as a way to produce biomarkers of aging. Older people with a predicted age that is higher than their chronological age, based on retinal imagery, exhibit a higher mortality rate. The growing diversity of clocks estimating biological age illustrate that just about every sizable set of biological data can mined to produce algorithmic combinations of data that correlate with mortality and incidence of age-related disease. Producing these clocks is the easy part of the task. It will be harder to calibrate and understand the clocks well enough to use them to assess the effectiveness of potential age-slowing and age-reversing therapies.

A growing body of evidence suggests that the network of small vessels (microvasculature) in the retina might be a reliable indicator of the overall health of the body's circulatory system and the brain. While the risks of illness and death increase with age, it's clear that these risks vary considerably among people of the same age, implying that 'biological ageing' is unique to the individual and may be a better indicator of current and future health, say the researchers.

Researchers turned to deep learning to see if it might accurately predict a person's retinal age from images of the fundus, the internal back surface of the eye, and to see whether any difference between this and a person's real age, referred to as the 'retinal age gap', might be linked to a heightened risk of death. The researchers drew on 80,169 fundus images taken from 46,969 adults aged 40 to 69, all of whom were part of the UK Biobank, a large, population-based study of more than half a million middle aged and older UK residents. Some 19,200 fundus images from the right eyes of 11,052 participants in relatively good health at the initial Biobank health check were used to validate the accuracy of the deep learning model for retinal age prediction.

This showed a strong association between predicted retinal age and real age, with an overall accuracy to within 3.5 years. The retinal age gap was then assessed in the remaining 35,917 participants during an average monitoring period of 11 years. During this time, 1,871 (5%) participants died: 321 (17%) of cardiovascular disease; 1018 (54.5%) of cancer; and 532 (28.5%) of other causes including dementia. The proportions of 'fast agers' - those whose retinas looked older than their real age - with retinal age gaps of more than 3, 5, and 10 years were, respectively, 51%, 28%, and 4.5%. Each 1 year increase in the retinal age gap was associated with a 2% increase in the risk of death from any cause.


The Failure of the Single Disease Paradigm in the Treatment of Aged Patients

Medical research and development in the context of aging has, like all other medicine, been dominated for a long time by a model in which a single disease is identified by symptoms and then treated. In the context of infectious disease and inherited conditions, this is a good way to go about the matter of investigation, treatment, and assignment of resources. A patient typically has one disease at a time, and the symptoms are distinct and clearly caused by the disease in question. Indeed, the disease paradigm arose from the modern era's long road towards ever more effective control of infectious disease. The institutions and traditions created over that time were then turned, as-is, to the question of aging and age-related diseases.

Here, however, the disease paradigm fails miserably. Age-related diseases arise from shared causes, the underlying mechanisms of aging. Attempting to treat symptoms, the downstream consequences of accumulating cell and tissue damage, produces only modest gains rather than functional cures. Further, most aged patients exhibit multiple, interacting conditions arising from the same root causes, making it even more inefficient to try to apply the single disease model of diagnosis and treatment. Physicians and researchers specialize in only one small set of downstream consequences, and rarely interact meaningfully with other specialties.

It is far past time to move on to a better model for the research and development of therapies to treat aging and age-related disease, one focused more on underlying causes, in which there is a recognition of the mechanisms of aging as a primary target for intervention. Today's open access commentary is a discussion along these lines, but remains, I think, a little too fixated on the primacy of symptoms as a way to guide academia, industry, and clinic.

Why illness is more important than disease in old age

Currently the single disease paradigm is still dominant in medicine in general, and also plays a major role in geriatric reasoning. This paradigm (sometimes referred to as Occam's razor) aims to explain illness by looking at patients´ symptoms (subjective: e.g. pain) and clinical signs (objective: e.g. high blood pressure) in specific patient episodes and by linking these with a single disease. Thus, clinicians aim to identify the single best cause for a patient's constellation of symptoms. Diagnostic reasoning in geriatrics should however take into account the high prevalence of multimorbidity, which increases with age from around 10% at the age of 40 to 85% in those aged 75 and over. In older adults with multimorbidity, a single symptom may arise from multiple diseases (e.g. fatigue may arise from both heart failure and osteoarthritis). Parallel treatment of single diseases easily leads to a high total treatment burden, over-treatment and aggravation of disease burden due to drug-drug, drug-disease, and drug-nutrition interactions. Thus, in case of multimorbidity, the cumulative single disease approach is often inefficient and potentially harmful.

Despite the great urgency, geriatric medicine still lacks a valid and clinically applicable model for adequate diagnosis, prognosis, and treatment of multimorbidity. Commonly used epidemiological methods try to explain multimorbidity pathophysiology by using sum scores, morbidity indices, and clustering of diseases. Clinically, multimorbidity is taken into account by cumulative (sometimes weighted) comorbidity scores, if considered at all. However, these epidemiology-based methods all fail to capture the dynamics and complexity of multimorbidity and its impact on the individual patient. Moreover, these methods are quantitative, abstract figures that do not inform clinical decision-making and thus are of limited added value in clinical practice. Even the most advanced models still rely on clustering of single disease concepts, and do not explain the interactions in multiple organ systems.

Complex systems thinking implies that illness in case of multimorbidity is not caused by a simple sum of single diseases and may offer an alternative explanatory model to the biomedical model. The science serving this field is devoted to understanding the general properties of complex systems. Core hallmarks of complex systems include: [1] networks of interacting elements (e.g. interactions among aging mechanisms such as oxidative stress and amyloid aggregation in dementia or decreased mobility, depressed mood, and joint pain), [2] feedback/feedforward loops (e.g. adaptive loops such as blood pressure regulation and maladaptive loops such as higher inflammatory states in Alzheimer's disease or older COVID-19 patients), [3] a multiscale or modular hierarchical structure (e.g. accumulating cellular damage nested within organ tissue, within organisms and families), [4] non-linear dynamics (e.g. tipping points in disease trajectories that cause acute flipping from dementia to a delirious state) and [5] emergent properties: the sum of properties of system components is not equal or even similar to the whole system outcome (e.g. well-being and illness cannot be understood simply as the sum of multiple morbidities as we diagnose them when they occur individually).

We therefore propose to develop clinical dynamic symptom network (DSN) based using principles of complexity science and network analysis. First evidence for the clinical utility of this approach comes from mental health research, in which the single disease model often fails and complex psychological symptom networks have advanced understanding and treatment of mental disorders. DSNs may form the foundation of a new paradigm to understand and treat geriatric illness episodes and trajectories. These should not replace geriatric syndromes or disease thinking, but may have a strong synergistic value, as thinking in symptoms and an illness concept may be more closely related to improving well-being outcomes in older patients. In future research, DSNs may be used to: (i) understand the complex, time-varying interrelations of symptoms, signs and diseases; (ii) develop prognostic models for changes in symptoms, signs and diseases over time; and (iii) evaluate effects of therapeutic interventions on the total symptom burden.

The Metabolome as a Biomarker of Aging in Flies

One of the many approaches to building a clock that can determine biological age is to mine the data of the metabolome, the levels of various small molecule metabolites used and generated by cells. Shifts in the metabolome will reflect age-related changes in function and cell behavior. As is the case for all such clocks, finding a good correlation with mortality and morbidity in the data using machine learning approaches doesn't provide any insight into why these relationships exist. That makes it challenging to use such a clock to assess potential interventions to slow or reverse aging, as it is by no means clear that a given clock will usefully reflect the outcome of a given intervention targeting only one or a few of the mechanisms important in aging.

Many biomarkers have been shown to be associated not only with chronological age but also with functional measures of biological age. In human populations, it is difficult to show whether variation in biological age is truly predictive of life expectancy, as such research would require longitudinal studies over many years, or even decades. We followed adult cohorts of 20 Drosophila Genetic Reference Panel (DGRP) strains chosen to represent the breadth of lifespan variation, obtain estimates of lifespan, baseline mortality, and rate of aging, and associate these parameters with age-specific functional traits including fecundity and climbing activity and with age-specific targeted metabolomic profiles.

We show that activity levels and metabolome-wide profiles are strongly associated with age, that numerous individual metabolites show a strong association with lifespan, and that the metabolome provides a biological clock that predicts not only sample age but also future mortality rates and lifespan. This study with 20 genotypes and 87 metabolites, while relatively small in scope, establishes strong proof of principle for the fly as a powerful experimental model to test hypotheses about biomarkers and aging and provides further evidence for the potential value of metabolomic profiles as biomarkers of aging.


TDP-43 Implicated in Amyotrophic Lateral Sclerosis

TDP-43 is one of the more recently discovered problem proteins in the aging brain, capable of misfolding and aggregating in ways that promote neurodegeneration and the onset of dementia. This occurs to at least some degree in all older individuals, but where this aggregation is particularly pronounced it can give rise to conditions such as amyotrophic lateral sclerosis. Here, researchers report on their investigations of the biochemistry of this dysfunction, providing further evidence for TDP-43 aggregation to cause the onset and progression of amyotrophic lateral sclerosis.

Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intramuscular nerves from ALS patients and in axons of human iPSC-derived motor neurons of ALS patient, as well as in motor neurons and neuromuscular junctions (NMJs) of a TDP-43 mislocalization mouse model.

In axons, TDP-43 is hyper-phosphorylated and promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis in distal axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondrial proteins are reduced. Clearance of axonal TDP-43 or dissociation of G3BP1 condensates restored local translation and resolved TDP-43-derived toxicity in both axons and NMJs. These findings support an axonal gain of function of TDP-43 in ALS, which can be targeted for therapeutic development.


Prior Replacement of Microglia Reduces Brain Injury and Inflammation Following Hemorrhagic Stroke

Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. Like macrophages, microglia are involved in tissue maintenance and repair, as well as in clearance of molecular waste and destruction of pathogens. Interestingly, microglia are one of the classes of immune cell that, similarly to B cells, will repopulate quite rapidly following selective destruction. That destruction is now routinely achieved in animal models using small molecule CSF1R inhibitors.

When this destruction and replacement is performed in old animals, the new microglia lack many of the undesirable features characteristic of microglia in old tissues, and behave in a more youthful fashion. Senescent microglia are removed, but there are likely other beneficial differences before and after.

This has attracted some interest in that part of the research community involved in finding ways to address the aging of the brain. As shown in today's open access research, when this microglial replacement is accomplished prior to brain injury, it can reduce the normal, unhelpful, inflammatory reaction to that trauma. Lasting inflammation and disruption of brain tissue function are reduced. This is perhaps a measure of the degree to which aged microglia are biased towards harmful inflammation.

Microglial replacement in the aged brain restricts neuroinflammation following intracerebral hemorrhage

Inflammation is a critical aggravator of neural injury following brain insults. In the aged brain, microglia exhibit an exaggerated and uncontrolled inflammatory phenotype in response to brain insults or immune stimulation. Rather than an enhanced immune response at baseline level, aged microglia possess a primed profile that is demonstrated by augmented production of inflammatory factors such as interleukin (IL)-1β and reactive oxygen species following stimulus. Although evidence suggests a link between the primed profile of the aged microglia and vulnerability of the old brain to inflammation-related secondary injury following acute insult, it remains poorly understood to what extent the aged microglia with a primed profile can impact the neuroinflammation and the outcome of acute brain injury.

The survival of microglia critically depends on signaling through the colony-stimulating factor 1 receptor (CSF1R). Administration of CSF1R inhibitor PLX3397 eliminates microglia in the whole brain that continues when CSF1R inhibition is present. Moreover, removal of CSF1R inhibition stimulates the rapid repopulation of the entire brain with new microglial cells, leading to effective replacement of the entire microglia population, a process takes approximately 2-3 weeks to complete.

Recent evidence suggests that withdrawal of CSF1R inhibitors in the old mice leads to complete repopulation of new microglia with characteristics resembling young microglia. Therefore, withdrawal of CSF1R inhibitors in the old brain resets the primed microglia and provides an opportunity to determine the impact of aged microglia on neural injury upon brain insults. In this study, we investigated the impact of microglial replacement in the aged brain on neural injury using a mouse model of intracerebral hemorrhage (ICH) induced by collagenase injection.

We found that replacement of microglia in the aged brain reduced neurological deficits and brain edema after ICH. Microglial replacement-induced attenuation of ICH injury was accompanied with alleviated blood-brain barrier disruption and leukocyte infiltration. Notably, newly repopulated microglia had reduced expression of IL-1β, TNF-α, and CD86, and upregulation of CD206 in response to ICH. Our findings suggest that replacement of microglia in the aged brain restricts neuroinflammation and brain injury following ICH.

Treating the Causes of Aging Seen through the Lens of Treating Multimorbidity

This popular science article takes an approach that seems useful when presenting the argument for treating aging as a medical condition to people who are entirely unfamiliar with the concept. At present the practice of medicine treats the symptoms of aging only, addressing each symptom - each age-related condition - separately. But most old people have numerous conditions, stemming from the same underlying causes, the causative mechanisms of aging. It only makes sense to address age-related conditions more efficiently, and the path to that goal is to target these deeper causes of aging, thereby treating numerous age-related conditions with one intervention.

Over half of UK adults over the age of 65 live with two or more long-term health conditions - commonly known as multimorbidity. Crucially, over half of GP consultations and hospital appointments involve patients with multimorbidity. In the UK, care for people with multimorbidity is also estimated to take up to 70% of health and social care expenditure.

Multimorbidity is currently managed by treating each disease separately. This means people will need to take multiple medications at the same time (known as polypharmacy), and will also have to attend multiple medical appointments for each condition. Not only can this put a strain on the NHS, polypharmacy can also put patients at increased risk of negative drug interactions and unintended harm. There's a clear need to improve the way multimorbidity is treated. But research shows that to do this, we need to instead start looking at targeting the key causes of multimorbidity when searching for treatments.

Although multimorbidity differs for each person, we know that patients tend to suffer from the same groups of diseases - known as "clusters". This suggests that each cluster may share a common underlying cause. For example, a person with multimorbidity may suffer from heart problems (such as heart disease and high blood pressure) and diabetes, which may all stem from the same cause - such as obesity. Identifying and treating the cause of a patient's disease clusters would allow us to more effectively combat several - or even all - of the diseases a patient has using a single treatment.

Such an approach has not yet been taken, in large part because medical research and drug discovery tends to focus on treating a single disease. Importantly one of the biggest risk factors for developing multimorbidity is getting older. This is why researchers think targeting the biological causes of ageing could be one way of treating multimorbidity, by preventing clusters of diseases from developing in the first place.

For example, we become less able to remove senescent cells from our body as we get older, causing them to accumulate and increase our risk of disease. Researchers think that if we could prevent these cells from building up, we may be better able to prevent multimorbidity from happening to begin with. Drugs which can kill senescent cells (called senolytics) already exist, and are currently used to treat certain types of leukaemia, and are now being trialled on patients with the chronic lung condition idiopathic pulmonary fibrosis. Given that senolytics are already in clinical use, this means they could quickly be repurposed for use in patients with multimorbidity if proven to be effective on other conditions too.


Does NAD+ In Fact Decline With Age Sufficiently to be a Useful Target for Interventions?

Nicotinamide adenine dinucleotide (NAD) is an important part of the mechanisms by which mitochondria produce chemical energy store molecules to power cellular processes. NAD levels fall with age, concurrent with growing mitochondrial dysfunction. There is some enthusiasm for approaches - such as supplementation with vitamin B3 derivatives - that might compensate for this issue and thereby improve mitochondrial function in later life.

Researchers here suggest that in fact the quality and quantity of evidence for NAD+ levels to decline with age doesn't rise to the level that the scientific community should by using as a basis to proceed towards the development of interventions. I think it most likely that more rigorous work will confirm the existing evidence. More pertinent objections to sizable investment in NAD upregulation are that (a) exercise increases NAD levels to a greater degree than any of the other approaches assessed to date, and (b) the results of clinical trials of NAD upregulation are decidedly mediocre.

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with age. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to increase NAD+ levels to promote vitality and protect against age-related diseases.

This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.


Blocking Olfactory Receptors in Macrophages Reduces Inflammation in Blood Vessel Walls

Chronic inflammatory signaling is an important issue in aging, both generally throughout the body, and in localized hot spots such as atherosclerotic lesions in blood vessel walls. Macrophage cells responsible for clearing out molecular waste and repairing damage in blood vessels are made less effective by inflammatory signaling. The feedback loop of ineffective macrophages becoming incapacitated by the toxic lesion environment, while inflammation draws in more macrophages, is at the center of the progression of atherosclerosis. Ultimately these fatty lesions grow to the point of rupture, and the result is a heart attack or stroke.

In today's research materials, scientists report on a less well studied component of inflammation, in that macrophages express olfactory receptors also found in cells in the nose, and can identify aldehydes in the bloodstream. The cells react with raised inflammatory signaling. The presence of such compounds increases with age, and this contributes to the growing dysfunction of macrophage cells that should be working to keep blood vessel walls free from metabolic waste and damage.

A cautionary note on this front is that past efforts to treat atherosclerosis by suppression of inflammatory signaling did not produce exceptional results. The outcomes looked little better than therapies that lower LDL cholesterol in the bloodstream, producing only a minor reduction in the size of existing lesions. Since mortality risk scales with the size and number of lesions, the great unmet need here is a way to rapidly and safely remove lesions. Present strategies can only slow the condition, and do little for the high risk groups in which patients already exhibit sizeable lesions.

Immune cells can sniff out octanal in blood, triggering dangerous inflammation and atherosclerosis

Everyone has a small amount of octanal in their blood, but scientists have shown that people with markers of cardiovascular disease, such as high LDL cholesterol, also have higher levels of octanal. This extra octanal can end up in blood due to diet or a phenomenon in cells called oxidative stress. The human nose is already good at smelling octanal. A 2019 study was the first to show that macrophages in blood vessel walls also have some of the olfactory receptors needed to "smell" molecules. These macrophages can sense octanal, thanks to an olfactory receptor called OR6A2. The new study is the first to show precisely how sniffing out octanal can boost inflammation in the arteries.

Researchers tested the effects of injecting octanal into wild type mice and into mice where the gene for the mouse macrophage receptor Olfr2 (which corresponds to OR6A2 in humans) was deleted. By comparing these mouse groups, researchers found that inflammation gets much worse as the Olfr2 receptor senses octanal. Over time, the arteries even begin to develop the lesions seen in atherosclerosis. The researchers then used a molecule called citral (which has a lemon-like odor), known to block this mouse olfactory receptor, and saw that inflammation went down. By making macrophages blind to octanal, they reversed the disease progression.

Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production

Atherosclerosis is an inflammatory disease of the artery walls and involves immune cells such as macrophages. Olfactory receptors (OLFRs) are G protein-coupled chemoreceptors that have a central role in detecting odorants and the sense of smell. We found that mouse vascular macrophages express the olfactory receptor Olfr2 and all associated trafficking and signaling molecules. Olfr2 detects the compound octanal, which activates the NLRP3 inflammasome and induces interleukin-1β secretion in human and mouse macrophages.

We found that human and mouse blood plasma contains octanal, a product of lipid peroxidation, at concentrations sufficient to activate Olfr2 and the human ortholog olfactory receptor 6A2 (OR6A2). Boosting octanal levels exacerbated atherosclerosis, whereas genetic targeting of Olfr2 in mice significantly reduced atherosclerotic plaques. Our findings suggest that inhibiting OR6A2 may provide a promising strategy to prevent and treat atherosclerosis.

Retrotransposon Activity in Neurodegeneration

In recent years, researchers have investigated retrotransposon activity in the context of aging. Retrotransposons, a class of transposable element, are sequences in the genome capable of replication, perhaps archeological debris from the ancient interactions of cells and viruses, co-opted by evolution. Transposable elements are largely suppressed in youth, but the suppression mechanisms become less effective in later life, one of countless cellular mechanisms that runs awry for reasons that are far from fully understood. It is a challenge to connect specific changes in gene expression to specific underlying causes of aging; a cell is a system in which everything interacts with everything else. Cellular metabolism is far from fully mapped at the detail level, even before considering the ways in which metabolism - and the surrounding microenvironment that a cell reacts to - accrues damage and shifts with age.

The etiology of aging-associated neurodegenerative diseases (NDs), such as Parkinson's disease (PD) and Alzheimer's disease (AD), still remains elusive and no curative treatment is available. Age is the major risk factor for PD and AD, but the molecular link between aging and neurodegeneration is not fully understood. Aging is defined by several hallmarks, some of which partially overlap with pathways implicated in NDs. Recent evidence suggests that aging-associated epigenetic alterations can lead to the derepression of the LINE-1 (Long Interspersed Element-1) family of transposable elements (TEs) and that this derepression might have important implications in the pathogenesis of NDs.

Almost half of the human DNA is composed of repetitive sequences derived from TEs and TE mobility participated in shaping the mammalian genomes during evolution. Although most TEs are mutated and no longer mobile, more than 100 LINE-1 elements have retained their full coding potential in humans and are thus retrotransposition competent. Uncontrolled activation of TEs has now been reported in various models of neurodegeneration and in diseased human brain tissues. We will discuss in this review the potential contribution of LINE-1 elements in inducing DNA damage and genomic instability, which are emerging pathological features in NDs. TEs might represent an important molecular link between aging and neurodegeneration, and a potential target for urgently needed novel therapeutic disease-modifying interventions.


An FDA Regulator's View of the Issues with the FDA in the Matter of Treating Aging

A charitable view of the FDA is that it is populated by well-meaning people who happen to believe that (a) any cost in lives, time, and funds is worth it in order to prevent harm by commission, and (b) zero risk is a possible goal in medicine. The Hippocratic Oath Enforcement Agency, if you like. There are much less charitable views, given the present state of regulatory capture that dramatically raises costs and slows development, as well as the invisible graveyard of countless lives lost to the absence of medical technologies that would otherwise exist and be widely available at reasonable prices.

There is no established regulatory path to approval for treatments that target aging. So at present biotech and pharma companies working on therapies that target mechanisms of aging pick a single age-related disease in order to gain regulatory approval. It is assumed that there will be widespread off-label use thereafter. There are efforts underway to pave a better road, but this will take a good long time at the usual glacial pace of large regulatory agencies.

An endocrinologist by training, Kitalys Institute founder Alexander Fleming is well qualified to take on the regulators. He spent more than a decade at the FDA, where he led the medical reviews that resulted in approval of drugs including metformin, as well as the first statin, insulin analog, and PPAR agonist. Getting approved longevity and geroscience therapies into the public domain is what Kitalys and its conferences and initiatives are all about. No easy task, as Fleming is all too aware. "I think we have some unique challenges in the geroscience domain, in particular the kind of evidence that will be required for regulatory approval. It's going to take a much longer clinical trial to get the evidence to show that the product is working, and not just on the typical endpoint that would be used to approve a drug."

One of the key challenges in geroscience and interventions that target aging is that, unless an intervention truly reverses a disability or something that people already are experiencing, then it will require very long studies to show the benefit. The first such longevity trial, the TAME trial on metformin, is about to commence, led by Nir Barzilai. "Nir and his colleagues are about to embark on a trial that could run three to five years to show an effect across multiple chronic diseases. But here's the thing - we can't expect metformin to produce more than very small effects in slowing the onset of each chronic disease. The premise of the TAME trial is that putting these small effects together in a composite endpoint will show that metformin is doing something sooner than it would be possible to demonstrate an effect on the individual diseases. Still, these effects, even when summed will never be noticed by the individual. But that is what we need - we need that data. So, that's really what we're striving to do - to create an environment that will produce that data. Part of that is having clear regulatory pathways that define the goal posts."

Kitalys is already engaged in what he considers to be two major educational projects. "One is to the regulatory authorities themselves. It's not that they are antagonistic to the development of geroscience products. They are enthralled by the science, but they're scratching their heads as to what they're being asked to do. So, we want to help them on that front. The other educational project involves the people on the other side, particularly those either in the lab or trying to do translational work, and who feel that the regulators are part of the problem. And that's not really true - the regulators are simply reflecting the reality that it takes a long time to get evidence to justify approval of products that may require decades of individual use to provide full benefit." Fleming believes that both sides need to understand each other's predicament and challenges.


Reviewing the Role of Cellular Senescence in Liver Disease

Senescent cells are play a role in the onset and progression of near every age-related condition. Cells become senescent constantly throughout the body and throughout life, most because they have reached the Hayflick limit to replication. In youth, senescent cells are efficiently removed, either through programmed cell death or by the immune system. With age, the immune system declines in effectiveness. Senescent cells begin to linger and grow in number. These errant cells secrete a mix of pro-growth, pro-inflammation signals that, when present over the long term, disrupt cell and tissue function.

Today's open access review takes a look at senescent cells in the aging liver, and their contribution to liver disease. While human trials have yet to be undertaken for liver conditions, it is plausible that selectively destroying senescent cells using senolytic therapies will prove to be beneficial to patients. This is true of so many different age-related conditions that the research and development community has started in on clinical trials for only a small fraction of them.

Thus there is a role for philanthropy here, to take presently available, low-cost senolytic therapies such as the dasatinib and quercetin combination and run low-cost, rapid trials of efficacy for dozens of age-related conditions. With proof that this can help patients with specific issues, more physicians will be open to prescribing senolytic therapies off-label, and we may see many more aged people benefit sooner than would be the case if the field is left to established institutions.

Biliary Epithelial Senescence in Liver Disease: There Will Be SASP

Cellular senescence is a pathophysiological phenomenon in which proliferative cells enter cell cycle arrest following DNA damage and other stress signals. Natural, permanent DNA damage can occur after repetitive cell division; however, acute stress or other injuries can push cells into premature senescence and eventually a senescence-associated secretory phenotype (SASP). In recent years, there has been increased evidence for the role of premature senescence in disease progression including diabetes, cardiac diseases, and end-stage liver diseases including cholestasis. Liver size and function change with aging, and presumably with increasing cellular senescence, so it is important to understand the mechanisms by which cellular senescence affects the functional nature of the liver in health and disease.

Cholangiocytes, which are morphologically heterogenous, polarized cells lining the biliary epithelium, have high absorptive/secretory functions and play a role in the 1) modification of canalicular bile, 2) paracrine communication with portal cells, and 3) regulation of immune cell infiltration. Cholangiocytes are the target of various liver diseases such as fatty liver diseases: non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), and chronic cholestatic liver diseases including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), biliary atresia, and cholangiocarcinoma. Biliary secretory functions regulate liver inflammation and fibrosis (by both autocrine and paracrine pathways) through secretion of cytokines and other factors which may contribute to liver damage. Cellular senescence increases in cholangiocytes of PSC patients, likely contributing to disease progression.

Chronic Stress Accelerates Atherosclerosis

Sustained psychological stress is shown to accelerate the progression of atherosclerosis. The most plausible biological explanations involve the effects of stress on (a) the immune system, resulting in raised inflammatory signaling, and on (b) blood pressure. Raised blood pressure can accelerate atherosclerosis, as well as raise the risk of rupture of atherosclerotic lesions. The relationship between stress and atherosclerosis may well have as much to do with the lifestyle effects of stress and their downstream effects on cardiovascular health over the long term, however.

Although the specific biological mechanisms by which chronic stress increases cardiovascular disease risk remain unclear, chronic low-grade inflammatory load appears as a possible link. Chronic stress exacerbates this load and leads to early progression of atherosclerosis and thrombotic complications. Inflammation plays a key role in the overall atherosclerotic step, involving the accumulation of foam cells, the formation of fatty stripe tissue and fibrous plaques, the rupture of acute plaques, and the formation of thrombus. Persistence of inflammation is necessary for plaque development and instability, and plays a decisive role in the pathogenesis and progression of coronary artery disease.

Studies have shown that chronic stress-induced hyperlipidemia and oxidative damage can contribute to the development of atherosclerosis. Although atherosclerosis is a chronic inflammatory disease, hyperlipidemia is a major risk factor for changes in intimal and media thickness during atherosclerosis. Experiments have found that compared with the control group, the high concentrations of serum total cholesterol, triglyceride, low density lipoprotein cholesterol (LDLC), and very low density lipoprotein cholesterol (VLDLC) could increase the atherosclerosis index in the chronic stress group, while the concentration of high density lipoprotein cholesterol did not change significantly.

Chronic stress plays a very important role in the development of hypertension, and its mechanisms are known to involve long-term abnormal neurological and endocrine activity, such as significantly elevated levels of corticosteroids, cortisol, epinephrine, norepinephrine, and angiotensin. Initially, the sympathetic nerve-adrenal medulla system is an important factor in the development of hypertension. Under chronic stress, plasma adrenaline, norepinephrine, and dopamine increase rapidly. It is now clear that in hypertension, the sympathetic nervous system activity is increased, and sympathetic excitation causes small arteriovenous contractions, leading to an increase in diastolic/systolic blood pressure.


FOXO3 in Cardiovascular Disease

FOXO3 is one of the few genes in which variants correlate with human longevity in multiple study populations. Effect sizes are still small of course, meaning a modest adjustment to the odds of reaching very old age, but one can at least look into the role of FOXO3 and say something about processes likely to be important in human late life mortality. Evidence suggests that FOXO3, while influencing very general cell behaviors such as stress responses, is involved in vascular aging. Cardiovascular disease is the largest cause of human mortality. That said, it seems unlikely that there is any basis for effective therapy in a deeper examination of FOXO3; the effect of variants on human longevity just isn't large enough.

Forkhead box O3 (FOXO3) has been proposed as a homeostasis regulator, capable of integrating multiple upstream signaling pathways that are sensitive to environmental changes and counteracting their adverse effects due to external changes, such as oxidative stress, metabolic stress, and growth factor deprivation. FOXO3 polymorphisms are associated with extreme human longevity. Intriguingly, longevity-associated single nucleotide polymorphisms (SNPs) in human FOXO3 correlate with lower-than-average morbidity from cardiovascular diseases in long-lived people.

Healthy aging is critical for addressing the increasing severity of global population aging. The unique role of FOXO3 in the vasculature provides promising avenues for therapeutics against aging-related vascular diseases. Post-translational modifications that regulate FOXO3 activity may be potential therapeutic targets. It is expected that research into strategies for delaying the occurrence and development of vascular aging by targeting the FOXO3 will uncover novel perspectives for the development of new drugs.

Despite advances in our understanding of FOXO3's function in retarding vascular senescence, the particular processes remain poorly known, and other issues remain unresolved. For instance, FOXO3 activation promotes vascular smooth muscle cell apoptosis, which may result in atherosclerotic plaque instability and rupture, causing myocardial infarction, and cerebral infarction. In some cases, FOXO3 promotes extracellular matrix degradation which may accelerate the progression of atherosclerosis. While therapies targeting FOXO3 seem appealing, we need to understand all the details to maximize its effectiveness. Despite these challenges, in-depth research into FOXO3 functions may pave the way for future therapeutic approaches.


Altos Labs Officially Launches with $3 Billion in Funding to Tackle In Vivo Reprogramming

Altos Labs was formed to develop in vivo reprogramming into a viable class of therapies to treat aging. Reprogramming occurs during embryonic development, and the discovery of the Yamanaka factors allows this process to be enacted in any cell. To date this has largely been used in the development of induced pluripotent stem cells, a source of cells for research and therapy. The other effects of reprogramming are coming to be just as interesting, however: a resetting of the epigenetic marks characteristic of cells in old tissues, and a restoration of mitochondrial function. Studies in mice show that partial reprogramming, reversing epigenetic aging while not converting cells into stem cells, produces benefits. Can this be made safe enough for use in humans? Therein lies the question.

As the launch announcement indicates, Altos Labs is shaping up to be a sizable project, populated by luminaries from academia and industry. It may have more committed funding at this point than the whole of the rest of the nascent longevity industry. It is likely an interesting story, yet to be told, as to how exactly in vivo reprogramming, of all of the possible approaches to the treatment of aging, gained so much support among high net worth individuals interested in aging as a field of development. If these funds are spent well, the next decade will see all of the immediate questions answered regarding the use of in vivo reprogramming as a therapy.

The present big picture understanding of reprogramming is an interesting one. It may be the case that cycles of DNA damage and repair lead, via the usual indirect routes of cellular biochemistry, to much of the characteristic epigenetic change that occurs with age. In which case resetting those epigenetic marks is indeed a form of repair and rejuvenation, of a similar scope as senolytic therapies that remove senescent cells and their negative impact on metabolism. Reprogramming cannot repair DNA damage, it cannot do much for accumulations of metabolic waste that even young cells cannot break down, such persistent cross-links and lysosomal aggregates. But it may well achieve enough to be worth the effort to develop a safe implementation for human medicine.

Altos Labs launches with the goal to transform medicine through cellular rejuvenation programming

Altos Labs (Altos) launched today as a new biotechnology company dedicated to unraveling the deep biology of cellular rejuvenation programming. Altos' mission is to restore cell health and resilience to reverse disease, injury, and the disabilities that can occur throughout life. The company launches with a community of leading scientists, clinicians, and leaders from both academia and industry working together towards this common mission. Altos launches with $3B fully committed from renowned company builders and investors.

The Altos executive team will be composed of Hal Barron, MD (incoming CEO), Rick Klausner, MD (Chief Scientist and Founder), Hans Bishop (President and Founder), and Ann Lee-Karlon, PhD (Chief Operating Officer). Hal Barron is currently President of R&D and Chief Scientific Officer at GSK and will join Altos as CEO and Board co-chair effective August 1, 2022. Klausner was former director of the National Cancer Institute and entrepreneur, Bishop was former CEO of GRAIL and Juno Therapeutics, and Lee-Karlon was former Senior Vice President at Genentech.

Altos will be initially based in the US in the San Francisco Bay Area and San Diego, and in the UK in Cambridge. The company will also have significant collaborations in Japan. Set within these geographies, activity will be organized across the Institutes of Science and the Institute of Medicine. The Altos Institutes of Science will pursue deep scientific questions and integrate their findings into one collaborative research effort. The Altos Institute of Medicine will capture knowledge generated about cell health and programming to develop transformative medicines.

"Altos seeks to decipher the pathways of cellular rejuvenation programming to create a completely new approach to medicine, one based on the emerging concepts of cellular health. Remarkable work over the last few years beginning to quantify cellular health and the mechanisms behind that, coupled with the ability to effectively and safely reprogram cells and tissues via rejuvenation pathways, opens this new vista into the medicine of the future. Altos begins with many of the leading scientists who are creating this new science. Together, we are building a company where many of the world's best scientists can collaborate internally and externally and develop their research with the speed, mission, and focus of private enterprise. Our success will depend upon a culture of intense collaboration, enthusiasm, and openness."

A Cautious View of the Benefits of Senolytic Therapies

Senolytic therapies to selectively destroy senescent cells in old tissues have produced rapid rejuvenation in mice, turning back many different age-related diseases in many different studies. Senescent cells actively maintain a disrupted, inflammatory state of tissue when not cleared effectively by the immune system. Initial human trials of the dasatinib and quercetin combination (readily available to self-experimenters as well, prescribed off-label) have produced promising results. But as the authors of this paper note, there is still far too little human data to satisfy the cautions of regulators. Many more trials should be underway, particularly for dasatinib and quercetin, to definitively establish that this is a path worth pursuing, and allow the physician community to prescribe senolytics widely in the aged population.

Over the past decade, it has become clear that tissue ageing is caused by the accumulation of senescent cells, which alters the physiological responses in the surrounding microenvironment in an autocrine and paracrine fashion through the senescence-associated secretory phenotype (SASP). The body of evidence showing that elimination of senescent cells seemed to be largely beneficial led to huge research efforts to identify novel agents that eliminate senescent cells in humans. However, the repurposing of existing drugs and the use of new senotherapeutics are associated with various side-effects; incomplete functional characterisation of peripheral tissues at systemic administration; an absence of standardised guidelines for timing, dose, and route of administration; and a paucity of efficacy and safety data from clinical trials. Therefore, the full potential of senotherapeutics has been hampered in clinical applications.

It is likely that the best senotherapeutic against age-associated diseases and malignancies is yet to be discovered. Dasatinib, quercetin, and other senolytics were discovered using a mechanism-based approach. High throughput screening technology, which allows for automated testing of thousands of molecules present in chemical compound libraries in in-vitro senescence models, could assist with the discovery of new effective senolytics. To date, high throughput screening of commercial chemical compound libraries has led to the discovery of new families of senolytics: HSP90 inhibitors,the BET family protein degraders, and cardiac glycosides.

Furthermore, the safety and potency of existing senolytics can be improved by molecular engineering and drug delivery approaches. For example, the use of ABT263 is limited due to dose-limiting platelet toxicity. Researchers devised a proteolysis-targeting chimera technology to reduce the platelet toxicity of ABT263 by converting it into PZ15227. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo. Similar strategies might be useful to improve the efficacy and the safety profile of other toxic or repurposed senolytic agents.

In conclusion, senolytic drugs have shown promising results in the elimination of senescent cells and in alleviating various diseases in animal models. However, in patients, there is a paucity in data on the efficacy and safety of senotherapeutics from clinical trials, including systemic effects and side-effects. In this regard it is important to assess the specificity of senolytics in killing targeted senescent cells and their cytotoxic effects, to identify reliable markers for intervention responses, to elucidate interactions with comorbidities and other drugs, and to standardise administration protocols.


Alzheimer's Disease Associated Genetic Variants Have Varying Correlations with Longevity

As a general rule, one should take with a grain of salt the results of any individual study on gene variants and correlations with longevity or disease risk. The results rarely replicate. Longevity in particular is a complex emergent phenomenon, and any one gene variant has only a small effect, highly dependent on interactions with environment and other genes. If anything, more rigorous studies of large genetic databases have been steadily decreasing the estimated contribution of genetic variants to variations in human life span. It is near all a matter of culture and lifestyle choice. That said, there are a few well defined gene variants that correlate with Alzheimer's disease risk, those examined in this paper. One should just be a little dubious as to whether the modest correlations with longevity will replicate in other study populations.

Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer's disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single nucleotide polymorphisms (SNPs) in cognitively healthy centenarians, and replicated findings in a parental-longevity genome-wide association study (GWAS).

We found that 28 of 38 SNPs that increased AD-risk also associated with lower odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. Based on these distributions, we grouped the SNPs in three groups: 17 SNPs increased AD-risk more than they decreased longevity-risk, and were enriched for β-amyloid metabolism and immune signaling; 11 variants reported a larger longevity-effect compared to their AD-effect, were enriched for endocytosis/immune-signaling, and were previously associated with other age-related diseases. Unexpectedly, 10 variants associated with an increased risk of AD and higher odds of longevity.

Altogether, we show that different AD-associated SNPs have different effects on longevity. Most AD-associated variants that increase the risk of the disease are associated with lower odds of longevity. We identified a subset of variants with a larger effect on longevity than on AD, that were previously associated as risk-factors for other age-related diseases, and that are selectively enriched for endocytosis and immune signaling functions, and expressed in microglia and endothelial cells.


NAD+ Depletion Primes Cells for Inflammatory Behavior

Today's open access paper provides an interesting view on the age-related reduction in cellular NAD+ levels, a topic of interest in the longevity community these past years. Nicotinamide adenine dinucleotide (NAD) is an important piece of molecular machinery in the function of the electron transport chain in mitochondria. The primary role of mitochondria is to generate the chemical energy store molecule adenosine triphosphate (ATP), used to power the cell. NAD cycles between NAD+ and NADH during this process, and lower levels of NAD imply a growing dysfunction in cellular energy metabolism.

Separately, researchers here show that lowered levels of NAD act to prime a cell for inflammatory activity. Mitochondrial dysfunction with age may affect levels of chronic inflammation in tissues via this mechanism. As we all know by now, chronic inflammation sustained over years provides a sizable contribution to degenerative aging, disrupting the normal processes of tissue maintenance, changing cell behavior for the worse, and accelerating many of the common age-related conditions.

Given this, it is interesting that fairly direct, compensatory restoration of NAD levels via the various approaches based on supplementation of vitamin B3 derivatives (niacin, nicotinamide riboside, nicotinamide mononucleotide, and so forth) perform so indifferently in clinical trials. They do not address deeper causes of this age-related decline, but do compensate in the production of more NAD. That said, exercise is better at restoring NAD levels in older people. Equally exercise produces numerous other beneficial effects on metabolism and cell function. The challenge in thinking about any newly considered mechanism of aging is, at the end of the day, whether or not it has a large effect size. The evidence for effect size is often indirect and dubious.

Intracellular NAD+ Depletion Confers a Priming Signal for NLRP3 Inflammasome Activation

Intracellular nicotinamide adenine dinucleotide (NAD+) levels steadily decline with age in both rodents and humans. NAD+ is an essential electron acceptor in several redox reactions that maintain intracellular homeostasis. NAD+ also functions as a cofactor for non-redox NAD+-consuming enzymes, such as poly-ADP-ribose polymerases (PARPs) and sirtuins (SIRTs).

NAD+ is synthesized either from tryptophan in the de novo pathway or by recycling nicotinamide (NAM) in the salvage pathway. In mammals, the salvage pathway is the predominant source of NAD+ biosynthesis due to its high adaptability. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ biosynthesis in the salvage pathway, converts NAM to nicotinamide mononucleotide (NMN), which is subsequently converted into NAD+ by NMN adenyltransferase. Reduced NAMPT expression at both mRNA and protein levels has been observed in multiple tissues during aging and is primarily responsible for the aging-associated NAD+ decline.

NAD+ decline is implicated in the pathophysiology of various diseases, including metabolic, cardiovascular, and neurodegenerative diseases. The supplementation of NAD+ using NAD+ pathway intermediates attenuates these degenerative disorders. Thus, NAD+ biosynthesis can be a potent therapeutic target for many aging-associated diseases. However, it is unclear whether NAD+ depletion can trigger or promote chronic proinflammatory responses that are closely associated with increased susceptibility to aging-associated diseases. Of note, a previous study showed that NAD+ depletion inhibits lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) signaling in human monocytes. Similarly, inhibition of NAMPT (using FK866, a NAMPT-specific inhibitor) modulated the proinflammatory responses in macrophages.

In this context, we assessed whether FK866-induced NAD+ decline can modulate pattern-recognition receptor (PRR)-mediated responses in myeloid cells. Consequently, we propose that NAD+ depletion can trigger NLRP3 activation in macrophages and induce in vitro and in vivo inflammasome activation in the presence of NLRP3-activating stimuli.

More Funding for the Dog Aging Project

There is a growing enthusiasm for aging research and the development of interventions aimed at slowing or reversing aging. This has reached the point at which people with significant resources are becoming involved, and thus the more prominent projects in the research and development communities are gaining support that would have been hard to find just a few short years ago. This new funding for the Dog Aging Project is a good example of the growing level of support for work on aging, undertaken by people who have bought into the vision of a future in which medical technology allows for much longer, healthier lives for all.

The Dog Aging Project, a scientific initiative to help companion dogs and people live longer, healthier lives together, has received a $2.5 million pledge from a consortium of tech entrepreneurs. The Dog Aging Project brings together a community of dogs, owners, veterinarians, researchers, and volunteers to carry out the largest canine health study in the world. The donation will expand this research into longevity science. The donors include Brian Armstrong, Coinbase founder and CEO; Peter Attia, physician; Juan Benet, Protocol Labs founder and CEO; Fred Erhsam, co-founder of Paradigm and Coinbase; Adam Fisher of Bessemer Venture Partners; author Tim Ferriss and the Saisei Foundation; Jed McCaleb, Stellar co-founder and CTO and founder of the Astera Institute; and food author Darya Rose and internet entrepreneur Kevin Rose.

The Dog Aging Project has two fundamental goals: first, to understand how genes, lifestyle, and environment influence aging; and second, to intervene to increase healthspan, the period of life spent free from disease. Discoveries made by the Dog Aging Project could be translatable to people. More than 32,000 companion dogs and their owners are already part of the Dog Aging Project. All the dogs live and play at home with their families. Most of these dogs participate in the observational Longitudinal Study of Aging. Each dog owner completes extensive surveys about the health and life experience of their dog through a secure research portal. This information is paired with comprehensive environmental, genetic, and biochemical data to yield insights about aging.

In addition, the Dog Aging Project is conducting a double-blind, placebo controlled, veterinary clinical trial of the medicine rapamycin, which at low doses has been shown to extend lifespan in laboratory animals. The trial is called TRIAD, an acronym for Test of Rapamycin in Aging Dogs. The $2.5 million in new funding provided by the consortium of donors will go directly to scientific research. This support will allow the Dog Aging Project to expand the TRIAD Trial to include more study locations and to increase the number of dogs enrolled in TRIAD.


Gameto Raises $20M at an Early Stage to Focus on Ovarian Aging

One of the signs of investor enthusiasm for an industry is the existence of projects that raise significant funding at a very early stage of their development. We're seeing that happen for cellular reprogramming, but companies started by well-connected individuals in other parts of the longevity industry are now raising a great deal of funding in early preclinical stages of development. This suggests that we will continue to see a growing influx of capital into the development of ways to treat aging as a medical condition, pulling more research projects out of the constraints of academia and into an environment of greater funding and attention. We can hope that an acceleration of progress across the field will result from this.

A small but growing group is also beginning to focus on menopause, which impacts half the population and whose onset is associated with a long list of health conditions, from higher blood pressure, LDL cholesterol and triglycerides, which is a form of fat in the blood, to, even more frighteningly, a greater risk of breast cancer, heart disease, and osteoporosis.

The newest outfit focused on the cause is Gameto, which says it wants to solve the problem of "accelerated" ovarian aging to change the trajectory of women's health and equality. Ovaries age up to five times faster than any organ in the sense that they stop working far earlier than, say, the liver, or brain, or even skin. While women are born with a certain number of ovocytes - an immature female sex cell that later gives rise to a fully mature ovum or egg cell - they eventually run out of these, at which point their ovaries stop functioning as an organ and stop producing the hormones that control women's physiology.

One-year-old Gameto wants to help delay that process, or even push it off forever if a woman chooses, by developing a platform for ovarian therapeutics that will initially be used to improve the process of assisted fertility but hopefully, eventually, be used, too, to identify cell therapies that can prevent the medical burden of menopause. How exactly? It's still early days and the Gameto principals are loath to dive into specifics, but the young company has already begun testing whether ovarian supporting cells could help mature eggs and reduce the number of IVF cycles that women often endure currently. Some notable investors are willing to bet on that early evidence. New York-based Gameto just raised $20 million in funding led by Future Ventures. Other participants include Bold Capital Partners, Lux Capital, Plum Alley, TA Ventures, Overwater Ventures, Arch Venture Partners co-founder Robert Nelsen and 23andMe CEO Anne Wojcicki.


Request for Startups in the Rejuvenation Biotechnology Space, 2022 Edition

For some years now, I've offered a yearly set of suggested projects for new startups in the rejuvenation biotechnology space. Or, alternatively, it might be viewed as a series of lengthy complaints about the slow pace of process towards human rejuvenation, given the many opportunities that exist. That slow pace is particularly galling in the case of the lowest-hanging fruit, a range of therapies that have been practical to carry out for at least a few years now, and yet have still not been meaningfully assessed for their ability to produce at least some degree of rejuvenation in aged humans. Given that the level of funding available to for-profit and non-profit ventures in the treatment of aging has increased dramatically in the last year, it is coming time to be much more aggressive about setting up and running clinical trials.

No More Reprogramming Startups for a Few Years

An enormous amount of funding is now devoted to the topic of in vivo reprogramming of cells. Altos Labs and NewLimit alone represent more than three billion dollars of interest. All of the important questions that stand open on the topic of cellular reprogramming as a potential path to rejuvenation are likely to be answered in the decade ahead. If you have an interest in starting a venture to advance the state of the art, pick another promising area that needs support and funding to make progress.

Elements of an Alternative Clinical Trial Ecosystem

In the last few years, scores of low cost clinical trials for age-related diseases could have run for the existing senolytic treatment of dasatinib and quercetin alone. Those trials have not been undertaken largely because there is not enough profit in this to interest large players in the industry. It takes so much funding to achieve regulatory approval that many therapies are simply not economically viable. Then we have Khavinson peptides for thymic regrowth, gut microbiome rejuvenation via a few different methods, and other comparatively straightforward approaches likely to improve health in late life, and which are also lacking the low cost clinical trials needed to produce convincing demonstrations of efficacy. This, again, is largely because it is seen as challenging to make enough profit from these interventions to justify the cost of regulatory approval.

Yet the component parts of a separate, parallel ecosystem of simple proof-of-efficacy trials and treatment via medical tourism that can successfully operate at a fraction of the cost of the formal regulatory system in the US and Europe all exist today: clinics; funding organizations; alternative credible regulatory systems in smaller countries; many people interested in seeing progress. Such an alternative could carry forward these and other potentially useful therapies, those that are suppressed by the economics of regulation in the US and Europe. It has yet to be stitched together into a functional whole, and to do so would be a worthwhile achievement

Rejuvenating the Gut Microbiome

Rejuvenation of the gut microbiome produces large enough effects on life span in short-lived species to suggest that it is interesting to pursue in humans, given how little the various demonstrated approaches cost, and how ready they are to proceed immediately to the clinic. Fecal microbiota transplantation and flagellin immunization are not complex technologies, but we do lack initial clinical trials to show robust benefits in older people. These trials would not be costly to run in a hundred people or so, considered in the grand scheme of things, and success in reducing age-related inflammation and improving other measures of health would enable a variety of business models.

Prove the Merits of the Khavinson Peptides

Various forms of the Khavinson peptides have been used in Russia for quite some time. Some are shown to regrow the atrophied thymus in aged animal models, thereby improving immune function. Some have caught the eye of the small community of self-experimenters that uses peptides in the hope of obtaining health benefits. The published Russian data on reduction of mortality in aged human patients is interesting, though lacking sufficient assays to support thymic regrowth or immune restoration. It is nonetheless perhaps enough to think that where there is smoke there is fire. One could start a clinical company given good results in human trials in the US or Europe, and it would not be excessively expensive to run a trial with a few hundred participants.

Deliver Proven Senolytics to the Masses

It has been several years since the combination of dasatinib and quercetin was shown to reduce senescent cells in humans in much the same way as it does in mice. The animal data continues to roll in, showing impressive reversal of age-related pathology in models of many conditions. Yet the research community is conducting very few clinical trials, and those under way are slow to publish. Dasatinib and quercetin are cheap and can be used legally off-label. There is nothing standing in the way of the formation of a physician network and clinical businesses that provide senolytics to patients. Running small, low cost, rapid trials to prove efficacy and confirm the known safety profile in humans would pave the way to bringing the first senolytic drugs to many of the older people who could benefit.

A Validated Consensus Clock for Biological Age

Clocks to assess biological age are proliferating rapidly. None can yet usefully be applied to the only task that really matters, which is assessing how well a candidate rejuvenation therapy works in practice. This is because no-one understands how specific underlying mechanisms of aging produce specific epigenetic, transcriptomic, or proteomic changes. Without that connection, the only way to validate a clock for a specific class of therapy is to run calibrating life span studies. Without that calibration, the data produced by a clock is of little value, because it is unknown as to whether the clock accurately integrates the contribution of the mechanism of aging targeted by the rejuvenation therapy under evaluation. This is a problem that is blocking the entire industry; rapid assessment of rejuvenation therapies is desperately needed in order to optimize progress.

Restoring Youthful Elastin Structures

Elastin structure is complex and degrades with age, leading to tissue stiffness. Elastin is largely only laid down in skin and other elastic tissues during the developmental period of life. To restore this structure it will most likely be necessary to enlist cells to undertake the task in the same way as they did during early life. This may be quite the challenge, requiring reprogramming, manipulation of regulatory pathways, and greater knowledge of the biochemistry of elastin deposition. But it is very important. Loss of elasticity in skin is just the visible sign of far worse consequences inside the body.

More Cross-Link Breaking, and More Variety in Approaches to Cross-Link Breaking

The only near term path to finding out just how important cross-linking is in vascular aging, and other aspects of aging in which the structural properties of tissue change with time, is to develop and test a therapy that breaks persistent cross-links. This is not a well populated area of development: there is Revel Pharmaceuticals targeting glucosepane cross-links, the Novartis program targeting a specific form of cross-link that occurs only in the lens of the eye, and that is about it. There is plenty of room for competition, particularly in the type of approach taken to break down this unwanted, harmful molecular waste.

Temporary Chimeric Antigen Receptor T Cells Produced in the Body via mRNA Gene Therapy

Chimeric antigen receptors applied to T cells, known as CAR-T therapies, are expensive. Isolating a patient's T cells, culturing them, engineering them, and then returning them to the body is an undertaking, particularly when it must be carried out with the very high level of reliability and quality control required by regulators. CAR-T therapies do well in attacking many types of cancer, but can have side-effects due to the lasting presence of engineered immune cells that have become too zealous. Few chimeric antigens are completely specific for cancer, and other cells will be destroyed as well. The approach noted here is an interesting one: temporarily turn a patient's circulating T cells into CAR-T cells by delivering an mRNA gene therapy. This can minimize off-target effects, while still creating a period of days in which the immune system targets undesirable cell types for destruction.

Researchers have demonstrated a new approach with an mRNA preparation that reprograms T cells to attack heart fibroblast cells. Heart failure is often driven in part by these fibroblast cells, which respond to heart injury and inflammation by chronically overproducing fibrous material that stiffens the heart muscle, impairing heart function - a condition called fibrosis. In experiments in mice that model heart failure, the reduction in cardiac fibroblasts caused by the reprogrammed T cells led to a dramatic reversal of fibrosis.

The new technique is based on chimeric antigen receptor (CAR) T cell technology, which, until now, has required the harvesting of a patient's T cells and their genetic reprogramming in the lab to recognize markers on specific cell types in the body. These specially targeted T cells can then be multiplied using cell culture techniques and re-infused into the patient to attack a specific cell type. However, this standard CAR T cell strategy would be problematic when directed against heart failure or other fibrotic diseases in humans. Fibroblasts have a normal and important function in the body, especially in wound healing. CAR T cells that are reprogrammed genetically to attack fibroblasts could survive in the body for months or even years, suppressing the fibroblast population and impairing wound healing for all that time.

Therefore, in the new study, researchers devised a technique for a more temporary and controllable, and procedurally much simpler, type of CAR T cell therapy. They designed mRNA that encodes a T-cell receptor targeting activated fibroblasts and encapsulated the mRNA within tiny, bubble-like lipid nanoparticles (LNPs) that are themselves covered in molecules that home in on T cells. Injected into mice, the encapsulated mRNA molecules are taken up by T cells and act as templates for the production of the fibroblast-targeting receptor, effectively reprogramming the T cells to attack activated fibroblasts. This reprogramming is very temporary, however. The mRNAs are not integrated into T-cell DNA and survive within T cells for only a few days - after which the T cells revert to normal and no longer target fibroblasts.


Theorizing on the Contribution of the Gut Microbiome to Crocodile Longevity

Researchers studying the comparative biology of aging examine differences between species of varying life spans, in search of insights into mechanisms of aging and potential interventions that might slow or reverse aging in our own species. This is a slow process. Even given the discovery of specific mechanisms that likely contribute to greater longevity or resilience in a given species, it tends to be challenging to determine how large a contribution is made by those mechanisms, and quite speculative as to whether any given mechanism can be used as a basis for therapy in our species. Still, there are many areas of ongoing study in various species in this part of the field, with the paper here as a representative example.

Crocodiles are flourishing large-bodied ectotherms in a world dominated by endotherms. They survived the Cretaceous extinction event, that eradicated the dinosaurs who are thought to be their ancestral hosts. Crocodiles reside in polluted environments; and often inhabit water which contains heavy metals; frequent exposure to radiation; feed on rotten meat and considered as one of the hardy species that has successfully survived on this planet for millions of years. Another capability that crocodiles possess is their longevity. Crocodiles live much longer than similar-sized land mammals, sometimes living up to 100 years. But how do they withstand such harsh conditions that are detrimental to Homo sapiens?

Given the importance of the gut microbiome on its' host physiology, we postulate that the crocodile gut microbiome and/or its metabolites produce substances contributing to their hardiness and longevity. Thus, we conducted a literature search on this topic and herein, we discuss the composition of the crocodile gut microbiome, longevity, and cellular senescence in crocodiles, their resistance to infectious diseases and cancer, and our current knowledge of the genome and epigenome of these remarkable species. Furthermore, preliminary studies that demonstrate the remarkable properties of crocodile gut microbial flora are discussed.

Given the profound role of the gut microbiome in the health of its' host, it is likely that the crocodile gut microbiome and its' metabolites may be contributing to their extended life expectancy and elucidating the underlying mechanisms and properties of these metabolites may hold clues to developing new treatments for age-related diseases for the benefit of Homo sapiens.


Nanowarming of Vitrified Kidneys and Hearts

Long term low temperature storage of living tissue is an active area of research. Cryoprotectant perfusion allows tissues to vitrify on cooling, minimizing ice crystal formation and thus preserving the small scale structure that is vital to tissue function. The challenge of cooling to vitrification is largely the challenge of obtaining good perfusion of cryoprotectant throughout the tissue, something that is much less of an issue for an isolated organ or tissue sample than it is for an entire animal or human. The more significant challenges are those related to the goal of warming vitrified tissue while retaining full function.

The near term goal for reversible vitrification is to enable more cost-effective organ donation and transplantation. That organ transplantation is a very expensive, uncertain process, and the available supply of organs very limited, is due in large part to the inability to keep an organ alive for long outside the body. In the mid-term, the transplantation industry will expand to include the manufacture of universal off-the-shelf tissues and organs that can be transplanted into any individual, grown from stocks of engineered cells. The logistics of that industry will be greatly aided by the ability to indefinitely store manufactured tissues, rather than making them to order. In the longer term, reversible vitrification will be used to preserve people who are close to death, in the hopes that future medical technology will allow their repair and revival.

At present vitrification of a patient at death by the still small cryonics industry is a one-way trip; the hope for future medical technology includes the development of means to safely warm the patient as well as repair other issues. It is not unreasonable to think that a future in which aging can be reversed at a very late stage is also a future in which vitrified tissues can be warmed. Unfortunately, the most successful of early approaches to warming vitrified tissues, discussed in today's research materials, won't help the cryopreserved patients already vitrified in past years. It requires nanoparticles to be perfused into tissues with cryoprotectant at the time of cooling. It will, however, help to start the organ transplantation industry on the road towards the use and refinement of vitrification technologies, still an important goal.

Vitrification and Rewarming of Magnetic Nanoparticle-Loaded Rat Hearts

To extend the preservation of donor hearts beyond the current 4-6 hours, this paper explores heart cryopreservation by vitrification - cryogenic storage in a glass-like state. While organ vitrification is made possible by using cryoprotective agents (CPA) that inhibit ice during cooling, failure occurs during convective rewarming due to slow and non-uniform rewarming which causes ice crystallization and/or cracking. Here an alternative, "nanowarming", which uses silica-coated iron oxide nanoparticles (sIONPs) perfusion loaded through the vasculature is explored, that allows a radiofrequency coil to rewarm the organ quickly and uniformly to avoid convective failures.

Nanowarming has been applied to cells and tissues, and a proof of principle study suggests it is possible in the heart, but proper physical and biological characterization especially in organs is still lacking. Here, using a rat heart model, controlled machine perfusion loading and unloading of CPA and sIONPs, cooling to a vitrified state, and fast and uniform nanowarming without crystallization or cracking is demonstrated. Further, nanowarmed hearts maintain histologic appearance and endothelial integrity superior to convective rewarming and indistinguishable from CPA load/unload control hearts while showing some promising organ-level (electrical) functional activity. This work demonstrates physically successful heart vitrification and nanowarming and that biological outcomes can be expected to improve by reducing or eliminating CPA toxicity during loading and unloading.

Vitrification and Nanowarming of Kidneys

Vitrification can dramatically increase the storage of viable biomaterials in the cryogenic state for years. Unfortunately, vitrified systems ≥3 mL like large tissues and organs, cannot currently be rewarmed sufficiently rapidly or uniformly by convective approaches to avoid ice crystallization or cracking failures. A new volumetric rewarming technology entitled "nanowarming" addresses this problem by using radiofrequency excited iron oxide nanoparticles to rewarm vitrified systems rapidly and uniformly. Here, for the first time, successful recovery of a rat kidney from the vitrified state using nanowarming is shown.

First, kidneys are perfused via the renal artery with a cryoprotective cocktail (CPA) and silica-coated iron oxide nanoparticles (sIONPs). After cooling at -40 °C min-1 in a controlled rate freezer, microcomputed tomography (µCT) imaging is used to verify the distribution of the sIONPs and the vitrified state of the kidneys. By applying a radiofrequency field to excite the distributed sIONPs, the vitrified kidneys are nanowarmed at a mean rate of 63.7 °C min-1. Experiments and modeling show the avoidance of both ice crystallization and cracking during these processes. Histology and confocal imaging show that nanowarmed kidneys are dramatically better than convective rewarming controls. This work suggests that kidney nanowarming holds tremendous promise for transplantation.

UV Radiation and Cross-Linking Contribute to Elastosis in Aged Skin

The elasticity of skin emerges from the structural properties of the extracellular matrix maintained by skin cells, the fine details of the structure of elastin and collagen that become disrupted with age. Two of the more important contributions to skin aging are, separately, exposure to UV radiation and the formation of persistent cross-links. Cross-links emerge from advanced glycation end-products (AGEs), sugary metabolic waste that can persistently link molecules in the extracellular matrix, changing the properties of tissue.

Removing persistent cross-links is a tractable challenge, given suitable enzymes, though too few groups are at present working towards this important goal. A more challenging prospect is restoration of elastin, ensuring that the structure of the aged extracellular matrix is returned to a more youthful configuration. This is likely to require sophisticated control of skin cell behavior, to replicate the initial creation of elastin structures that takes place during the developmental period of life.

Skin aging is the result of superimposed intrinsic (individual) and extrinsic (e.g., UV exposure or nutrition) aging. Previous works have reported a relationship between UV irradiation and glycation in the aging process, leading, for example, to modified radical species production and the appearance of AGEs (advanced glycosylation end products) in increasing quantities, particularly glycoxidation products like pentosidine. In addition, the colocalization of AGEs and elastosis has also been observed.

We first investigated the combination of the glycation reaction and UVA effects on a reconstructed skin model to explain their cumulative biological effect. We found that UVA exposure combined with glycation had the ability to intensify the response for specific markers: for example, MMP1 or MMP3 mRNA, proteases involved in extracellular matrix degradation, or proinflammatory cytokine, IL1α, protein expression. Moreover, the association of glycation and UVA irradiation is believed to promote an environment that favors the onset of an elastotic-like phenomenon: mRNA coding for elastin, elastase, and tropoelastin expression is increased.

Secondly, because the damaging effects of UV radiation in vivo might be more detrimental in aged skin than in young skin due to increased accumulation of pentosidine and the exacerbation of alterations related to chronological aging, we studied the biological effect of soluble pentosidine in fibroblasts grown in monolayers. We found that pentosidine induced upregulation of CXCL2, IL8, and MMP12 mRNA expression (inflammatory and elastotic markers, respectively). Tropoelastin protein expression (elastin precursor) was also increased.

In conclusion, fibroblasts in monolayers cultured with soluble pentosidine and tridimensional in vitro skin constructs exposed to the combination of AGEs and UVA promote an inflammatory state and an alteration of the dermal compartment in relation to an elastosis-like environment.


Further Wrangling Over the Definition of Aging as a Disease

The World Health Organization (WHO) manages the International Classification of Diseases (ICD), which goes through revised editions every so often. Since regulatory agencies and healthcare payers use the ICD in determining just about everything regarding whether or not specific treatments are permitted, many groups involved in the development of therapies to treat aging are interested in seeing aging unambiguously added to the ICD. At the end of the day this has little to do with semantics and a great deal to do with finances: the availability of funding for research and development, the direct and indirect costs of gaining regulatory approval, and so forth. Needless to say, this is all proceeding much as things usually do in large bureaucracies - slowly and to no-one's satisfaction, with the likely end result being greater ambiguity and cost rather than less ambiguity and cost.

It was proposed to exclude the code 'Old age' MG2A from the latest version of the International Classification of Diseases, ICD-11, with the claim that equating old age to a disease could have the negative consequences of treating calendar age as a disease, raising concerns of ageism. Yet, in fact, the 'Old age' code is not a new ICD addition, or one that should raise special concerns of ageism. The synonymic designation of 'Senility' or 'Old age' was carried over from ICD-10 as it has been a rather technical designation that allowed to establish the cause of death, when it was difficult or impossible to establish other causes. In contrast to the earlier versions, the ICD-11 allows for diverse synonymic interpretations, including those that can be highly useful for a clinician treating older persons, such as 'Ageing', 'Senescence', 'Senile state', 'Frailty', and 'Senile dysfunction', which refer to a state of health but not the number in the passport.

It is becoming increasingly clear that pathological processes of ageing are the major risk factors, and even major underlying causes of mortality and morbidity from non-communicable diseases, and, as we learn from the recent pandemics, also from infectious diseases. To address these ageing-related risk factors, there is a new wave of research and development that seeks to develop new therapies or repurpose older therapies, with the aim to slow and reverse the damage of ageing - i.e. preventive, regenerative, and curative medicine. This research and development necessitates appropriate ICD coding.

The new ICD-11 makes important steps toward that goal, as it provides a double focus for improving the health of older persons. First, by including the old age, senescence, and senile debility in the general symptoms category to target the state of ageing-related ill health, and second by including 'Ageing-related' code in the aetiology or causality category to target the pathogenic ageing processes. Thus, far from discriminating against the rights of older persons and fostering neglect for their curative or preventive health care, the ICD-11 codes for old age and ageing-related causality do exactly the opposite: they draw the public and professional attention to the specific health problems of older persons and call to action to improve the prevention and cures specifically for older persons. Thus, these designations are the very opposite of ageism.


The Cambrian Biopharma Approach to Obtain Regulatory Approval of Drugs to Treat Aging

The approach outlined here by the Cambrian Biopharma principals isn't exactly a secret: at least the first part of the process is exactly the playbook for nearly every company working on interventions that target the mechanisms of aging. Since there is no established regulatory path to treat aging as a medical condition, companies must seek approval to treat a specific age-related condition. They pick the best choice of the scores that could be treated by slowing or reversing one or more mechanisms of aging. Most groups stop the future planning at that point, as the likely next step following regulatory approval will be widespread off-label use for any therapy that proves effective - and US regulators don't like companies talking about off-label use.

The interesting part of the Cambrian Biopharma plan is how to dovetail existing work on persuading regulators to accept a trial for aging, such as the TAME trial design, with the necessary first steps in gaining approval for the treatment of a single age-related condition. As the longevity industry moves forward, and more approaches reach the point of clinical trials, this sort of open discussion about how to bring the regulators into line with reality will be increasingly necessary. Working within the system like this is one approach. There is also an energetic faction that feels that regulatory arbitrage and medical tourism are more viable approaches, moving treatment to countries with less restrictive and less costly regulatory regimes in order to force change at the FDA through competition.

The Secret Cambrian Bio Master Plan to Build Drugs to Treat Aging (just between you and me)

Despite the enormous benefits to individuals and society from medicines that could keep people healthier for longer, the development of geroprotectors (aka drugs that prevent age-related decline) accounts for a tiny fraction (less than 1%) of research dollars. The most common reason cited for this under-investment is that "aging" is not a disease, therefore you can't run a trial to "slow aging." This simplistic statement misses the mark in a few ways. The real challenges we need to overcome are more nuanced. They are: (1) multi-disease prevention (i.e., "aging") trials are risky, expensive, and slow; and (2) we don't have the biomarker needed to run cost-effective prevention trials in healthy people.

Cambrian's strategy tackles both of these key challenges with what I call our 'Secret Master Plan'. Our plan has three stages: get approval for newly developed geroprotectors as treatments for existing diseases causing acute suffering to patients today. Then, when it's clear these drugs are safe, effective, and valuable, do the large and expensive trials to show that these medicines slow aging in at-risk (often older) people. Finally, we will use the huge amounts of data gathered from rigorous and controlled clinical trials to approve geroprotectors using a surrogate biomarker of multi-morbidity risk to help people in good health stay that way.

Longevity outsiders criticize any preventative medicine approaches because the clinical trials are long and expensive. Longevity insiders criticize our approach of starting with currently recognized diseases because they want to run aging studies now. Both of them are wrong. Prevention studies are both feasible and worth doing, but they can only start once the safety and commercial value of a drug has been established.

Because a geroprotection study of healthy people in middle age would take decades, our first preventative studies will involve older people at high risk for developing the major diseases of aging. A well-designed trial will deliver a clear yes or no answer on whether a drug reduces risk of multiple diseases in 3 to 5 years. Still a long time, but worth it to show that a geroprotector can extend healthspan in humans.

Philanthropically funded clinical trials are already contemplating this approach, most notably the TAME Trial which proposes to use metformin (an off-patent diabetes medicine that extends healthspan in mice) in elderly individuals to prevent them from developing new morbidities. The bar for new drugs still under patent will be higher than for old drugs like metformin, but new drugs intentionally designed to maximize longevity effects and increase safety will work much better than the field's first coincidental discoveries like metformin and rapamycin.

A multi-disease preventative taken by at-risk elderly people would be the best-selling drug of all time. In 2030, a drug approved only for people 75 and older would have a market size of over $30 billion per year even if that drug costs less than $1,000 annually (way cheaper than most other drugs and less than a cup of coffee per day in New York). The impact of such a drug would be priceless.

Senescent Cells Negatively Affect T Helper Cell Differentiation

The accumulation of senescent cells with age harms tissues and cell behavior throughout the body. Senescent cells generate a pro-growth, pro-inflammation mix of molecules, the senescence-associated secretory phenotype (SASP). Researchers are still comparatively early in the process of producing a complete list of problems caused by the SASP. One of the better studied SASP components is TGF-β, and here researchers demonstrates that it causes disarray in the normal behavior of T-helper cells of the adaptive immune system. Applying senolytic treatments that selectively destroy senescent cells can reverse this aspect of aging, along with many others that are caused in part by senescent cells.

Aging and senescence impact CD4 T helper cell (Th) subset differentiation during influenza infection. In the lungs of infected aged mice, there were significantly greater percentages of Th cells expressing the transcription factor FoxP3, indicative of regulatory CD4 T cells (Treg), when compared to young. TGF-beta levels, which drive FoxP3 expression, were also higher in the bronchoalveolar lavage of aged mice and blocking TGF-beta reduced the percentage of FoxP3+ Th in aged lungs during influenza infection.

Since TGF-beta can be the product of senescent cells, these were targeted by treatment with senolytic drugs. Treatment of aged mice with senolytics prior to influenza infection restored the differentiation of Th cells in those aged mice to a more youthful phenotype with fewer Th cells expressing FoxP3. In addition, treatment with senolytic drugs induced differentiation of aged Th toward a healing Type 2 phenotype, which promotes a return to homeostasis. These results suggest that senescent cells, via production of cytokines such as TGF-beta, have a significant impact on Th differentiation.


Incidence of Cognitive Impairment is in Decline

Rates of cognitive impairment in older people continue to decline, as noted in this study. The researchers attribute this to just about everything except improvements in medical technology, though it may well be the case that improvements in treatment and prevention of cardiovascular disease contribute to this slowed loss of cognitive function. The population is aging, however, and with an ever greater fraction of the population being old, the overall incidence of age-related disease is increasing even as individual risk falls. Further, present trends represent only incremental improvements; the development of new medical technology to treat the causes of aging is the only viable path to radical gains in health and life span.

A new nationally representative study found an abrupt decline in the prevalence of cognitive impairment among American adults aged 65 and older compared to the same age group a decade earlier. In 2008, 12.2% of older Americans reported serious cognitive problems. In 2017, the percentage had declined to 10.0%. To put this into perspective, if the prevalence of cognitive impairment had remained at the 2008 levels, an additional 1.13 million older Americans would have experienced cognitive impairment in 2017.

The study was based on 10 consecutive waves of the American Community Survey (2008-2017), an annual nationally representative cross-sectional survey of approximately half a million American respondents aged 65 and older, including both institutionalized and community-dwelling older adults. A total of 5.4 million older Americans were included in the study. In each year, respondents were asked to report if they had "serious difficulty concentrating, remembering, or making decisions." The rate of decline in cognitive impairment was steeper for women than men. Women experienced a decline of 23% over the decade, while their male peers had a 13% decline during that period.

Further analyses indicated that 60% of the observed decline in serious cognitive impairment between 2008 and 2017 was attributable to generational differences in educational attainment. Extensive previous research has concluded that every additional year of formal schooling lowers the risk of individuals eventually developing dementia. Compared to children born in the 1920s, Americans born in each successive decade had much greater opportunities to pursue post-secondary education.

However, the decline in the prevalence of cognitive problems was not entirely explained by generational differences in educational attainment, suggesting there may be other factors at play that warrant future research. The authors hypothesize several possible contributors to these positive trends, such as improvement across the generations in nutrition, declines in smoking and air pollution, and the phase out of leaded gasoline.


Neutrophils Provoke Damaging Inflammation and Scarring Following Heart Damage

The heart is not a very regenerative organ. Following damage, scarring rather than reconstruction results, leading to reduced function. This contributes to the high mortality resulting from a heart attack. While preventing heart attacks is a much better goal than clearing up the damage afterwards, the research community is nonetheless very interested in understanding how to sabotage this scarring process. Interfering in the activities of immune cells has seemed a promising path forwards. Heart attacks provoke lasting inflammation, and such unresolved inflammation is disruptive of regenerative processes.

In today's research materials, scientists discuss the role of neutrophils in creating an inflammatory feedback loop between bone marrow and heart following heart injury. Suppressing this feedback loop reduces the scarring that takes place following a heart attack in mice. This sort of inappropriate immune activity may be a useful target for approaches to enhance regeneration in other tissues as well.

First-responder cells after heart attack prompt inflammation overdrive

Neutrophils are definitely a key part of the problem. In an earlier study, researchers found that heart-attack patients with higher numbers of neutrophils in their blood upon hospital admission, or even after doctors restored blood flow, had the worst outcomes. However, because neutrophils are vital to all wound healing and infection fighting, their first-responder role in heart repair cannot be bluntly targeted for elimination. Instead, the team has zeroed in on signals sent to the immune response control center - the bone marrow - that trigger ramped-up production of neutrophils.

As part of that investigation, the researchers found that the first wave of neutrophils to arrive at the damaged heart consider the injury so severe that they sacrifice themselves to prevent further damage, releasing their entire contents - including proteins called alarmins. These alarmins in turn activate sensors in a second wave of neutrophils, priming those cells for more intense action. These primed neutrophils then do something unexpected: they reverse migrate from the heart to the bone marrow and release a proinflammatory protein there, which prompts stem cells in the bone marrow to churn out even more neutrophils - all processes that perpetuate inflammation at a time when it's no longer needed for heart repair.

In the most recent paper, experiments in mice using genetic techniques or drugs uncovered at least two potential targets to consider for intervention: limiting the primed neutrophils' reverse migration or suppressing neutrophils' release of the proinflammatory protein in the bone marrow. The studies showed that successful inhibition of either mechanism led to better cardiac outcomes and less scarring in the mice.

Retention of the NLRP3 Inflammasome-Primed Neutrophils in the Bone Marrow Is Essential for Myocardial Infarction-Induced Granulopoiesis

Acute myocardial infarction (MI) results in overzealous production and infiltration of neutrophils to the ischemic heart. Using a combination of time-dependent parabiosis and flow cytometry techniques, we first characterized the migration patterns of different blood cell types across the parabiotic barrier. We next induced MI in parabiotic mice by permanent ligation of the left anterior descending artery and examined the ability of injury-exposed neutrophils to permeate the parabiotic barrier and induce granulopoiesis in noninfarcted parabionts.

MI promoted greater accumulation of the inflammasome-primed neutrophils in the bone marrow. Introducing a time-dependent parabiotic barrier to the free movement of neutrophils inhibited their ability to stimulate granulopoiesis in the noninfarcted parabionts. Our data reveal a new paradigm of how circulatory cells establish a direct communication between organs by delivering signaling molecules (eg, IL-1β) directly at the sites of action rather through systemic release. We suggest that this pathway may exist to limit the off-target effects of systemic IL-1β release.

Life Biosciences Raises a Sizable Round of Funding

I'll note the recent Life Biosciences capital raise as an example of the dramatic increase in funding flowing into the longevity industry in the past year or so. The companies that started earlier, many of which are running multiple distinct programs aimed at various approaches to the treatment of aging, are reaching the point at which they need to pull in significant funding to prepare for and undertake their first clinical trials. That funding is increasingly available. This remains a young industry, yet to obtain regulatory approval for any of the therapies under development, but it is clearly a field of growing interest.

Life Biosciences, a pioneering life sciences company developing therapeutics that target the biology of aging, today announced the completion of a Series C financing of $82 million led by Alpha Wave Ventures. Senior management and founders invested in the Series C financing alongside longevity-oriented funds, seasoned investors, and experienced biotechnology scientists/entrepreneurs. Since its founding, Life Biosciences has raised over $158 million.

"Our three platforms are based on seminal research demonstrating that aging biology can be modified therapeutically. The Series C funding enables us to accelerate development of our innovative therapies for multiple aging-related conditions, and we expect to initiate first-in-human studies for our first drug candidate possibly as early as the end of 2022."

Proceeds from the Series C financing will be used to accelerate research and development activities in the company's three platforms that target fundamental biological mechanisms contributing to aging. The mitochondrial uncoupling platform is developing oral small molecules that are designed to increase metabolic rate and decrease fat accumulation in models of obesity and NASH. The chaperone-mediated autophagy (CMA) platform is developing oral small molecules that are designed to activate CMA and thereby remove unwanted proteins that accumulate during aging and contribute to multiple aging-related diseases including neurodegenerative diseases. The epigenetic reprogramming platform is developing therapies that are designed to induce the expression of three Yamanaka factors to reprogram the epigenome of cells to a younger state and thereby restore cellular function across a wide range of diseases such as glaucoma.


A Mutation Distinguishing Modern Humans from Other Primates Acts to Reduce Oxidative Stress and Inflammation

Humans are long-lived in comparison to other primates, despite exhibiting broad genetic similarity to our closest neighboring species. Our comparative longevity is thought to have evolved as a consequence of our intelligence and culture, allowing grandparents to contribute to the survival of descendants, and thus increasing the selection pressure operating in later life. Here researchers identify one genetic difference in modern humans that may contribute to greater longevity. Interestingly, it is absent from Neanderthals, an ancestral subspecies of human that one would also expect to exhibit a greater life span as a result of intelligence and culture changing the landscape of later life selection pressure.

Aerobic organisms face the challenge of oxidative damage caused by reactive oxygen species produced as metabolic by-products. Glutathione reductase (GR) is a critical enzyme for preventing oxidative stress and maintaining a reduced intracellular environment. Almost all present-day humans carry an amino acid substitution (S232G) in this enzyme relative to apes and Neanderthals.

Three Neanderthal genomes and one Denisovan genome have been sequenced to high quality. This makes it possible to identify genetic changes that characterize modern humans. Among the single-nucleotide substitutions on the lineage leading to modern humans, which alter protein sequences, approximately 100 are known to occur among all or almost all humans today but not in the archaic genomes available to date. One of these affects GR, which, in present-day humans, carries a glycine residue at position 232, whereas Neanderthals, Denisovans, and other primates carry a serine residue at this position.

We express the modern human and the ancestral enzymes and show that whereas the activity and stability are unaffected by the amino acid substitution, the ancestral enzyme produces more reactive oxygen species and increases cellular levels of transcripts encoding pro-inflammatory cytokines. We furthermore show that the ancestral enzyme has been reintroduced into the modern human gene pool by gene flow from Neanderthals and is associated with multiple traits in present-day people, including increased susceptibility for inflammatory-associated disorders and vascular disease.


Metabolic Defects in Myeloid Cells Contribute to the Chronic Inflammation of Aging

Today's commentary discusses recent research into age-related changes in myeloid cell lineages of the innate immune system. These cells are produced by hematopoietic stem cells in the bone marrow, and play important roles in immune function and tissue function throughout the body. With age, hematopoiesis becomes biased towards an ever greater production of myeloid cells at the expense of other immune cells, a problematic shift. As noted in this commentary, the changes also extend to the behavior of myeloid cells, and thus to the capabilities of the immune system.

The work here pinpoints one set of changes in myeloid cells outside the brain that nonetheless negatively affects cognitive function, most likely via increased inflammatory signaling. The chronic inflammation of aging is coming to be understood as an important contribution to neurodegeneration. Inflammation is a necessary and useful aspect of our biochemistry when it is present in the short term, in response to infection and injury, for example. When sustained over the long term, however, inflammation disrupts normal tissue function throughout the body - and inflammatory signaling originating outside the brain can pass the blood-brain barrier to alter the behavior of cells in the brain.

Myeloid Metabolism as a New Target for Rejuvenation?

The immune system is drastically affected with ageing. While the adaptive immune response comprising B-cells and T-cells is diminished, the innate immune system (i.e., cells of the myeloid lineage) shows an increase in the pro-inflammatory state, also known as "inflammaging". This chronic low-inflammatory state is mainly driven by macrophages and pro-inflammatory cytokines.

Cellular metabolism has emerged as a key player in the regulation of immune function, starting already at the level of myeloid versus lymphoid lineage decision and greatly affecting cellular behaviour in the mature immune cells. Several recent studies have suggested that an altered cellular metabolism in aged macrophages might directly contribute to the pro-inflammatory signature. However, the detailed mechanisms initiating this increased inflammation with aging remain unclear.

In a recent publication, researchers have elucidated this cascade using an impressive set of in vitro and in vivo experiments in mice and in human myeloid cells. They found that aged myeloid cells have a decrease in cellular respiration and a decrease in glycolysis, suggesting that aged myeloid cells undergo a general bioenergetic failure. The proposed driving cause is the increased prostaglandin E2 (PGE2) signaling in the ageing myeloid compartment, mediated by the age-dependent upregulation of EP2, one of the four PGE2 receptors.

Conditional knockout of EP2, specifically in the myeloid cells (EP2 cKO) of aged mice proves to be an effective strategy at multiple levels. First, it rescues the expression of some of the immune factors upregulated with age, both in the plasma and in the hippocampus. Second, the loss of EP2 also reduces glycogen levels, normalizing the metabolic state and the associated mitochondrial defects observed in old macrophages. A similar effect is also mimicked by directly inhibiting GYS1. Third, strikingly, aged EP2 cKO mice appear to be completely protected from a decline in hippocampal-related memory functions with ageing.

Overall, this data supports an upstream role of peripheral myeloid cells in orchestrating the process of brain ageing, underscoring the important cross-talk between the immune and the central nervous systems.

Comparing Some of the Most Widely Used Epigenetic Clocks

Epigenetic clocks assess biological age based on an algorithmic combination of the DNA methylation status at some number of CpG sites on the genome. Some changes in DNA methylation are characteristic of age, but at this time it is unknown as to how these changes relate to the underlying damage and dysfunction of age. Researchers here find that an epigenetic clock using few CpG sites performs about as well as those using many more sites when it comes to correlations with mortality risk. This is interesting, but it seems unlikely that a clock using a small number of sites will perform well as a way to assess whether or not a potential rejuvenation therapy is working. A specific rejuvenation therapy will likely address only one underlying cause of aging, and there is no reason to expect that any given small collection of CpG sites will react usefully to changes in that one cause of aging.

Three DNA methylation (DNAm) based algorithms, DNAm PhenoAge acceleration (AgeAccelPheno), DNAm GrimAge acceleration (AgeAccelGrim), and mortality risk score (MRscore), based on methylation in 513, 1030, and 10 CpGs, respectively, were established to predict health outcomes and mortality. In this study, we evaluated and compared the three DNAm algorithms and a frailty index (FI) in relation to prediction of mortality in a cohort of older adults. The three DNAm algorithms and the FI were positively correlated with each other and each of them was independently associated with all-cause and cause-specific mortality.

Whereas the first-generation epigenetic clocks were assessed solely by chronological age as the reference, PhenoAge and GrimAge were designed to better capture biological aging. Given that AgeAccelPheno and AgeAccelGrim are reflecting differences of estimated biological age and chronological age, their lack of correlation with chronological age in our study was predictable. Moreover, AgeAccelPheno and AgeAccelGrim were observed to be weakly correlated with FI.

In a previous study from the Lothian Birth Cohort 1936, higher DNAm GrimAge was associated with lower cognitive ability and brain vascular lesions in older age. Previous studies also reported that higher GrimAge and PhenoAge values were associated with an increase in physical function deficits and were correlated with poorer fitness, such as diminished grip strength and cardio-pulmonary function. Frailty is a consequence of a cumulative decline in many physiological systems and frail individuals are characterized by increased vulnerability to age-related disorders. The observed correlations of AgeAccelPheno and AgeAccelGrim with FI in the current study may reflect declines in multiple physiological systems beyond "normal aging".

One primary aim of developing DNAm biomarkers is finding an accurate, simple, and feasible method to predict mortality or lifespan. In that respect, MRscore, requiring methylation quantification at a much lower number of CpGs, by itself or in combination with some easy-to-determine frailty measure, such as FI, has potential capacity to be a practical and economic indicator for mortality risk stratification.


Arguing for Aging of the Gut Microbiome to Worsen the Burden of Cellular Senescence

We should expect most of the various different aspects of aging to strongly interact with one another, leading to worse outcomes. Degenerative aging accelerates as it progresses precisely because of such harmful interactions. Researchers here discuss a still novel view of the way in which age-related changes in the gut microbiome may lead to greater harms resulting from the burden of senescent cells present in aged tissues. Incidentally, both the aging of the gut microbiome and the accumulation of senescent cells have bidirectional relationships with age-related immune system dysfunction. Near all aspects of aging interact.

Understanding the relationship between the gut microbiome and healthy aging is fundamental to achieving systemic longevity. Cellular senescence - a major hallmark of aging - is a promising area of research that requires investigation with relation to microbial dysbiosis. As an inevitable, age-related process, cellular senescence can cause severe damage to the host upon accumulation, largely due to overexpression of the senescence-associated secretory phenotype (SASP) and associated metabolic dysregulation.

Data from recent findings suggest an intricate relationship to exist between the gut microbiome, cellular senescence, and skin health. This proposed relationship is anchored by the SASP and largely influences the aging phenotype and associated diseases. The skin is vulnerable to the accumulation of senescent cells due to its external exposures (e.g., UV radiation). Recent literature suggests senescence to partake in numerous cutaneous diseases, all of which compromise function of the skin and general health. The link between skin homeostasis and healthy aging is further supported by recent evidence demonstrating systemic detrimental effects from chronic senescence in the skin, likely through paracrine signaling. Moreover, the presence of bacterial metabolites in the skin due to the gut-skin crosstalk can disrupt skin health, one way being further aggravation of the SASP.

Recent investigation has drawn correlations between gut composition and cellular senescence and revealed a distinct microbial composition in the gut in response to senolytic treatment. However, additional studies are needed to advance knowledge on microbial composition and function in the presence of accumulated senescence. Metabolomics is one approach that can help characterize metabolites found systemically and in the skin in order to quantify the impact of specific metabolic activity on senescence.


A Simple, Sensible Position on the Treatment of Aging as a Medical Condition

If there is to be a simple, sensible, consensus position on the treatment of aging as a medical condition, it might run something like this. (a) If our species is going to put significant time and funding into this project, then it is much better to conduct research and development programs that are capable of achieving rejuvenation, rather than those that can achieve only a slowing of aging. (b) Similarly, more rejuvenation is better than less rejuvenation. We should aim to optimize the direction of development as early as possible. (c) At present it is challenging, slow, and expensive to assess the benefits produced by an alleged rejuvenation therapy, particularly in long-lived species such as our own. (d) Thus it is important to develop the capability to assess biological age immediately before and after treatment, via robust, accurate, low-cost approaches. (e) Epigenetic, transcriptomic, and proteomic clocks offer the most likely path to such a viable assessment of biological age. (f) Developing a consensus, validated clock should be a priority alongside development of the first few potential rejuvenation therapies to have performed well to date in mice.

The authors of today's open access paper argue much along these lines. The corresponding author, Vadim Gladyshev, is actually not that optimistic about the likely pace of progress towards meaningful human rejuvenation in our lifetimes. He nonetheless has a sensible attitude towards the bigger picture, one of a network of large-scale research and development programs that will ultimately lead towards many different successful interventions targeting the processes of aging.

Despite the great promise of clocks to assess biological age, and the proliferation of such clocks discovered via machine learning approaches, this technology is not yet capable of producing unbiased measures of the effectiveness of new therapies. The challenge is that researchers as yet have little idea as to what, in detail, causes specific age-related changes in the epigenome, transcriptome, and proteome. Thus any use of a clock to assess a new approach to therapy must first be calibrated against life span studies, in mice at the very least, before we can take any of the resulting data seriously. The research community should prioritize this area of research, along with the first few candidate rejuvenation therapies likely to produce a large enough reversal of biological age to test the clocks.

Emerging rejuvenation strategies-Reducing the biological age

As the most significant risk factor for human mortality, aging leads to functional decline, increased frailty, and elevated susceptibility to chronic disease. The current strategies for human lifespan extension can be divided into three major categories: (i) those that treat direct causes of mortality, (ii) those that slow down or attenuate the biological aging process, and (iii) those that achieve rejuvenation (i.e., the reversal of aging).

The first category involves treatments for age-related diseases, such as pharmaceuticals for COVID-19 in humans or age-related cancers in mice. Antibiotics, which single-handedly shifted the main cause of death in humans and extended lifespan by several decades, also belong to this category. The second involves lifespan extension in healthy individuals, without evident age reversal. One example in this category is lifespan extension caused by mild stressors such as heat, cold, or irradiation. The third category, rejuvenation, has long been regarded as the panacea for age-related diseases, but it has previously been deemed unrealistic.

While the first two major strategies have been extensively studied, very little is known about the systemic reversal of organismal aging. This is in part due to the lack of longitudinal data and validated quantitative readouts of rejuvenation, and also by the general belief that aging is inevitable and unidirectional. However, several putative rejuvenation therapies have recently been introduced that demonstrated age reversal as measured by aging biomarkers and physiological readouts. Despite these advances, whether systemic rejuvenation can be achieved by these approaches and how they can be translated to human applications remains unclear.

Distinguishing potential rejuvenation therapies from other longevity interventions, such as those that slow down aging, is challenging, and these anti-aging strategies are often referred to interchangeably. We suggest that the prerequisite for a rejuvenation intervention is a robust, sustained, and systemic reduction in biological age, which can be assessed by biomarkers of aging, such as epigenetic clocks. We discuss known and putative rejuvenation interventions and comparatively analyze them to explore underlying mechanisms.

Age-Related Changes in Phospholipid Composition of Cell Membranes

This open access paper surveys what is known of age-related changes in the phospholipid composition of cell membranes, a feature that has been studied in a range of different species. As a mechanism of aging, this is likely downstream of deeper causes of aging, while also producing its own very complex set of consequences. Those consequences are poorly understood, and will likely remain poorly understood for the foreseeable future. There are only so many researchers and so much time and funding. Picking apart the fine details of aging at the level of cellular operations, particularly processes that can in principle influence near every aspect of cellular metabolism, is a very long-term prospect. This is why the better path forward towards lengthening the healthy human lifespan is to target the known root causes of aging, rather than studying their spreading, highly complex web of downstream consequences.

The relationship between lipids and aging has been well recognized. The contents, composition, and metabolism of fatty acid (FA) are altered in aged or long-lived humans and model organisms. Moreover, studies in model organisms such as Caenorhabditis elegans have revealed that various FA species could extend lifespan when supplemented in the diet. These unsaturated FAs function mainly through classic longevity factors, such as DAF-16/FOXO3, SKN-1/Nrf2, and HSF-1/HSF1, to regulate healthspan and lifespan.

Despite these advances linking FA to longevity regulation, little is known about their mechanisms of action. Generally, FAs function through several major mechanisms, including signaling molecules, energy resources, substrates for post-translational modifications, and the components of complex lipids. Take oleoylethanolamine for example, it acts as a signaling molecule and regulates animal lifespan by direct binding and activation of the nuclear hormone receptor NHR-80. But to date, only a few FAs were found to exert their functions directly as signaling molecules, or as substrates for post-translational modifications. The majority of FAs are incorporated into complex lipids such as membrane lipids as their acyl chains, thus affecting the structure, composition, and function of the membrane. Therefore, it is conceivable that FAs may regulate lifespan by acting as the important components of membrane lipids, potentially linking membrane homeostasis to lifespan regulation.

Membrane lipids, mainly phospholipids (PLs; also known as glycerophospholipids), consist of the lipid bilayer that acts as barriers between the cell and environment, and between different cellular compartments. However, numerous studies suggest that the lipid bilayer not only function as structural barriers but also play crucial roles in the regulation of multiple cellular processes. Also, this idea is supported by the diversity of membrane lipids (different membrane lipid species and different acyl chains within certain membrane lipids), which is far more beyond the need for barrier function. In regard to the aging process, studies in several model organisms have reported the association of the contents and compositions of many membrane lipids with animal age, supporting potential roles for the membrane lipids in aging modulation. In this review, we focused on PLs and summarized recent advances that link PL homeostasis to the aging process and discussed their potential mechanisms of action.


Metabolic Coupling in the Aging Retina

An interesting perspective is presented in this open access paper, a discussion of the age-related decline in coupling of metabolism between different cell types in the retina. Cell metabolism cannot be considered in isolation for a given cell or cell type, particularly in the central nervous system, where, for example, supporting cells provide metabolites to neurons. As is the case for many aspects of aging, it is hard to draw clear lines of cause and effect between more fundamental forms of cell and tissue damage and downstream disruption of complex systems such as this within our biology.

One particular metabolic pathway of interest in various cell types is the process of Warburg glycolysis. This process was originally discovered in the 1920s by Otto Warburg, who made observations about large quantities of lactate production in the neuroretinal and tumor cells in the presence of oxygen. This usually occurs as part of an "organized duet" between two compartmentalized cell types. Traditional thinking has taught that one half of this duo, cells rich in glycolytic pathways, results in the end product of pyruvate. Subsequent fate ordinarily depends on the presence of oxygen and mitochondria; however, in certain cell types - including cancer cells, neurons, and photoreceptors - pyruvate is converted to lactate by lactate dehydrogenase. This abundance of lactate generated by these specialized cells feeds other supporting cells that have adapted to use lactate as a fuel source and NAD+ to support glycolysis.

Until recently, lactate was thought of as mainly a metabolic waste product, but its roles as a carbon source and energy substrate have slowly been uncovered in the past decade. The other half of this coupling phenomenon, oxidative phosphorylation, is responsible for energy production in various cells that act in a supportive manner to the more glycolytic cell types. One particularly interesting coupling phenomena that has been extensively studied is the lactate shuttling that occurs between astrocytes and neurons. In this system, astrocytes sense activity at a neuronal synapse and, as a result, deliver the energy substrate lactate to surrounding neurons.

Retinitis pigmentosa is characterized by a dysregulation within the metabolic coupling of the retina, particularly between the glycolytic photoreceptors and the oxidative retinal pigment epithelium. This phenomenon of metabolic uncoupling is seen in both aging and retinal degenerative diseases, as well as across a variety of cell types in human biology. In this review, we explored metabolic coupling between various cell types in the retina, how retinal degenerations progress through the breakdown of this metabolic coupling, how aging mirrors the loss of coupling seen in the degenerative conditions, and lastly the development of strategies aimed at renormalizing the metabolic coupling between photoreceptors and retinal pigment epithelium cells as an imprecision medicine therapeutic avenue.


Cancer, the Second Largest Cause of Human Mortality

After cardiovascular disease, cancer is the second most prevalent cause of death in our species. One of the most important parts of a future toolkit of diverse rejuvenation therapies is a robustly effective, low-cost universal cancer therapy, one that can be applied to near all cancers with little need for customization. The best approach to that end is likely some form of interference in telomere lengthening. Unlike other known differences in cancer cells, this is plausibly the one aspect of cancer biochemistry that is both vital and immune to mutational change. A cancer can evolve its way out from under many forms of treatment, but not one that blocks the means by which cells remain able to replicate. Without a way to lengthen telomeres, cells die after a given number of replications, even cancer cells.

As noted in today's open access paper, overall cancer incidence is rising as the number of older people increases. This is an expected consequence of success in raising life expectancy; cancer is an age-related disease. As the immune system declines in effectiveness and forms of damage spread in the body, there is an ever greater chance of cells suffering a combination of mutations and circumstances that leads to cancer. Meanwhile, the individual risk of cancer is declining and odds of survival following a cancer diagnosis are increasing, a consequence of both public health measures and improvements in medical technology.

Mutation and cancer are core features of the biochemistry of multicellular life. Evolution needs mutation, and stem cells require the ability to replicate without limit. Some species are much more resilient to cancer than ours, but cancer will never be entirely eliminated as a possibility given the way in which our biology functions. For so long as the ability for cells to replicate exists, there will be failures of regulation that allow that replication to run amok. Thus it will always be important to have a cost-effective, highly reliable universal cancer therapy. That such a thing does not yet exist imposes a vast cost in suffering, lives, and funds expended on medical treatment.

Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019

The results of this systematic analysis demonstrate the substantial and growing global burden of cancer, with patterns of burden differing by sociodemographic index (SDI) quintile. In 2019, cancer-related disability-adjusted life years (DALYs) were second only to cardiovascular diseases in their contribution to global disease burden, and in the high SDI quintile, cancer overtook cardiovascular disease to become the leading cause of DALYs. Between 2010 and 2019, the number of new global cancer cases and deaths increased by 26.3% and 20.9%, respectively. However, the largest percentage increases in cancer incidence and mortality during the last decade occurred in the lower SDI quintiles, likely reflecting ongoing epidemiologic transitions, demographic shifts, and disparities in cancer prevention, care, and control.

While the absolute burden of cancer grew from 2010 to 2019, global age-standardized incidence rates remained similar at -1.1% and mortality rates decreased by -5.9%. These age-standardized mortality results suggest cautious optimism that some progress may have been made in early diagnosis and cancer treatment globally during the last decade.

However, inequities in the distribution and growth of cancer burden around the world diminish this potential advancement and suggest that an acceleration of efforts to effectively address cancer burden are needed. Of particular concern, recent progress in reducing age-standardized incidence and mortality rates seems concentrated in higher SDI locations, while both rates are still trending upward in lower SDI locations. The increasing age-standardized incidence and mortality rates in lower SDI quintiles may reflect several factors, including shifting population age structures, increasing capacity for diagnosis and registration of cancer cases and deaths, and changes in cancer risk factors, such as metabolic, behavioral, environmental, and occupational exposures.

Antioxidant Effects of Stem Cell Exosome Therapy

Oxidative stress is the excessive generation of oxidizing molecules in tissues, which can cause a range of harms, reacting with important molecular machinery to harm cells and detrimentally alter cell function. Rising oxidative stress goes hand in hand with the chronic inflammation of aging; some of the underlying mechanisms are shared. Thus researchers find that therapies that alter cell behavior to reduce chronic inflammation, such as stem cell transplants and the use of exosomes derived from those stem cells, may also act to reduce oxidative stress in aged tissues.

Mesenchymal stem cell-derived exosomes have been under investigation as potential treatments for a diverse range of diseases, and many animal and clinical trials have achieved encouraging results. However, it is well known that the biological activity of the exosomes is key to their therapeutic properties; however, till date, it has not been completely understood. Previous studies have provided different explanations of therapeutic mechanisms of the exosomes, including anti-inflammatory, immunomodulatory, and anti-aging mechanisms.

The pathological effects of oxidative stress often include organ damage, inflammation, and disorders of material and energy metabolism. The evidence gathered from research involving animal models indicates that exosomes have antioxidant properties, which can also explain their anti-inflammatory and cytoprotective effects. In this study, we have summarized the antioxidant effects of exosomes in in vivo and in vitro models, and have evaluated the anti-oxidant mechanisms of exosomes by demonstrating a direct reduction in excessive reactive oxygen species (ROS), promotion of intracellular defence of anti-oxidative stress, immunomodulation by inhibiting excess ROS, and alteration of mitochondrial performance.

Exosomes exert their cytoprotective and anti-inflammatory properties by regulating the redox environment and oxidative stress, which explains the therapeutic effects of exosomes in a variety of diseases, mechanisms that can be well preserved among different species.


Will Interventions that Improve Mitochondrial Function Also Increase Cancer Risk?

You may recall some speculative discussion regarding whether or not upregulation of NAD+ to improve mitochondrial function might increase cancer risk in old people. Much of the slowdown of aging, from reduced metabolism to reduced stem cell function, and certainly including loss of mitochondrial function, may influence lifespan by reducing the risk of cancer, while at the same time ensuring a slow decline into organ failure.

This topic remains speculative, but if NAD+ upregulation does in fact increase cancer risk, then it is possible that other approaches to restore mitochondrial function will also have this outcome. It could go either way: one important consideration is that a treatment that globally improves mitochondrial function will also tend to improve immune function, and the immune system acts to suppress cancer. Also consider that exercise does more to upregulate NAD+, and thereby improve mitochondrial function, than any of the assessed pharmacological approaches - and exercise certainly does not increase cancer risk.

Nicotinamide adenine dinucleotide (NAD) precursors and sirtuin-activating compounds (STACs) are becoming popular among longevity-minded individuals. The misguided conception that raising NAD or sirtuin activity can only have positive effects on human physiology should be considered erroneous and even deleterious. Hype exists around molecules that appear to extend life or slow down the aging process; however, little regard is given to the aberrant side effects or diseases that the upregulation of some molecules or overexpression of some proteins can cause, such as cancer.

Clearly NAD is used in all cells, including cancer cells, to produce energy. The findings of this review paper suggest that NAD supplementation should be discussed with a healthcare practitioner if you have a strong family history of cancer, have cancer, or have had cancer. Any given subject should first speak to their healthcare provider when considering NAD and possibly perform screening tests. However, NAD may fend off many other age-related diseases and prevent cancer from developing, so developing strategies to purge senescent cells from the body prior to NAD supplementation should also be considered.

The pursuit to blindly raise sirtuin activity in the quest for longevity may also produce counterproductive results and may be misguided. However, cancer cells like normal cells require the same cellular machinery to function, and this review does not find that NAD nor sirtuins cause cancer but may simply assist fuelling cancer where present. Where it is shown that sirtuin or NAD inhibition shows beneficial effects against cancer progression, it does not infer those elevated levels of sirtuins or NAD assist in cancer progression but are simply part of the cancer progression. Raising sirtuin or NAD activity may increase disease penetrance, and further research is required to understand the complex mechanisms at play.


Provocative Data from Shared Epigenetic Clocks for Naked Mole Rats and Humans

Epigenetic clocks appear to perform quite well as a measure of chronological age in species that exhibit negligible senescence, meaning that they show little evidence of degenerative aging across much of their life span. Researchers recently published their work on epigenetic aging in lobsters, a species in which a first method of determining chronological age was only discovered comparatively recently. Today's open access paper covers epigenetic aging in naked mole rats, a eusocial species that can live up to nine times longer than similarly sized mammals, and maintains robust health across much of that life span.

Since epigenetic clocks are produced via machine learning techniques applied to data on epigenetic modifications to the genome, as the pattern of modifications appears at different ages, it remains an interesting question as to what exactly is being measured. What processes drive chronological epigenetic change in a negligibly senescent species? It is particularly curious that the researchers here managed to produce clocks that work in both naked mole rats and humans. What does this say about the mechanisms by which naked mole rats achieve robust and healthy longevity? Even in mice and humans, it is largely unclear as to how epigenetic change is produced by the damage and dysfunction of aging. Thus these questions remain to be answered.

DNA methylation clocks tick in naked mole rats but queens age more slowly than nonbreeders

This study describes seven epigenetic clocks for naked mole rats (NMRs), of which five are specific to NMRs (for different tissue types) and two are dual-species human-NMR clocks that are applicable to humans as well. The human-NMR clocks for chronological and relative age demonstrate the feasibility of building epigenetic clocks for different species based on a single mathematical formula. This further consolidates emerging evidence that epigenetic aging mechanisms are conserved, at least between members of the mammalian class.

On a phenotypic level, the NMRs appear to evade aging. Hence, we did not know whether they display epigenetic changes with increasing age. Our study clearly detected significant age-related changes in DNA methylation levels across the entire lifespan of the animal, even in relatively young animals. This contradiction between phenotypic and epigenetic aging could imply that age-related DNA methylation changes do not matter since they do not appear to correlate with any adverse functional consequences in NMRs. However, accelerated epigenetic aging has been correlated to a very wide range of pathologies and health conditions.

Alternatively, it could mean that while the NMR ages at a molecular level, as do all other mammals, it has developed compensatory mechanisms that counteract the consequences of these epigenetic changes. The NMR age-related CpGs that we identified, and the availability of epigenetic clocks, are valuable resources to resolve this question.

Further clues to NMR aging were also revealed from the three-way comparison of age-related CpGs between NMRs, primates, and mice. Although primates and NMRs are phylogenetically more distantly related than NMRs and the mouse, these relationships are not similarly manifested when it comes to longevity. Indeed, NMRs and humans are more akin to each other as they are both outliers with regards to lifespan expected from their adult size. Here, the three-way comparison revealed that the reason for the unusually long lifespans of NMRs and primates may lie in the coregulation of developmental and metabolic processes. Conversely, similarly regulated developmental genes between NMR and human may reflect neotenic features characteristic of these two species. Neoteny is defined as retention of juvenile features into adulthood. A shift towards longer development and retention of youthful tissue repair can lead to longevity.

Rejuvenating the Gut Microbiome of Aged Mice in Various Ways

The gut microbiome changes with age in a number of different ways that are detrimental to long term health. Firstly, inflammatory microbial populations increase in number, rousing the immune system to constant overactivation. Secondly, microbial populations capable of generating beneficial metabolites such as butyrate are reduced in number. Researchers here present additional evidence for the importance of reduced butyrate production in mouse aging. As it is possible to favorably adjust the gut microbiome via a number of strategies (such as fecal microbiota transplantation, flagellin immunization, and, in principle at least, suitable probiotics), this is an area of research to keep an eye on.

Here, we report the changes in gut microbial communities and their functions in mouse models during ageing and three rejuvenation procedures including co-housing of young and old mice, injection of young serum into old mice, and parabiosis between young and old mice. Ageing-induced changes in the composition of the gut microbiota are associated with various age-related disorders. However, the rejuvenating effects of altered gut microbiota on the presence of specific bacteria remain elusive. Here, we show the changes in key microbial communities and their functions during ageing and three rejuvenation procedures, and the increase in the healthy lifespan of aged mice by oral administration of Akkermansia muciniphila (AK).

Our results indicate that intestinal function, inflammation, and intestinal homeostasis of aged mice can be rescued by three rejuvenation intervention models. All rejuvenation procedures significantly increased the relative abundance of the butyrate producer Oscillospira in rejuvenated mice, while the abundance of the beneficial genus Akkermansia was significantly increased in rejuvenated mice only during co-housing and serum injection. In addition, we observed that the abundance of aged-specific genera, such as Paraprevotella, Prevotella, Odoribacter, Erysipelotrichaceae cc_115, Rikenellaceae AF12, and Helicobacter, was significantly decreased in all rejuvenated mice, suggesting that the relative abundance of young- and aged-specific bacteria was reversed in their young counterparts during the co-housing and parabiosis procedures.

It has been reported that a high abundance of Prevotella, Turicibacter, and Paraprevotella is associated with dysbiosis, chronic inflammation, and type 2 diabetes, suggesting that they increase the risk of inflammation. Defective intestinal function and inflammation in aged mice can be improved by gut microbiota remodelling, suggesting a causal link between age-related changes in the gut microbiome and age-dependent morbidities.

For effective anti-ageing, it is important to find an appropriate approach to specifically manipulate the microbiota. Although fecal microbiota transplantation has shown potential in the treatment of several diseases, it is a complex biological intervention and has intrinsic limitations, that is, it can use only feces from healthy donors that are free from diseases. In this study, we controlled the ageing-related phenotype by oral administration of a single microbe, AK. AK restores intestinal integrity by activating epithelial cells, thereby supporting the growth of other beneficial commensals.

Furthermore, our data shows that AK extends the healthy lifespan, as evidenced by the frailty index and restoration of muscle atrophy. Since the age-related inflammatory state is associated with a decrease in skeletal muscle size and function (sarcopenia), the decrease in inflammation caused by oral administration of AK may be involved in the restoration of muscle metabolic function.


Oligodendrocyte Precursor Cell Therapy Improves Stroke Recovery in Mice

Regenerative therapies capable of improving functional recovery following brain injury, such as that caused by stroke, are a priority in the research community. Cell therapies make up a sizable fraction of the research and development programs aimed at that goal. Here, researchers note the results of delivering oligodendrocyte precursor cells to the stroke-damaged mouse brain. Oligodendrocytes are involved in maintenance of the myelin sheathing necessary for nerve function, but introducing their precursor cells clearly produces a greater range of benefits, beyond increased remyelination, in the scenario of a brain injury.

Ischemic-induced white matter injury is strongly correlated with the poor neurological outcomes in stroke patients. The transplantation of oligodendrocyte precursor cells (OPCs) is an effective candidate for enhancing re-myelination in congenitally dysmyelinated brain and spinal cord. Nevertheless, mechanisms governing the recovery of white matter and axon after OPCs transplantation are incompletely understood in ischemic stroke.

In this study, OPCs were transplanted into the ischemic brain at 7 days after transient middle cerebral artery occlusion (tMCAO). We observed improved behavior recovery and reduced brain atrophy volume at 28 days after OPCs transplantation. Moreover, our results identified that myelin sheath integrity and endogenous OPCs proliferation and migration were promoted after OPCs transplantation. In addition, the improvement of neurite growth and synaptogenesis after OPCs transplantation in ischemic brain or OPC co-cultured neurons, potentially through the upregulation of Netrin-1, was indicated by increased protein levels of synaptophysin and postsynaptic density protein 95.

In conclusion, our studies suggested that engrafted OPCs promoted the recovery after ischemic stroke by enhancing endogenous oligodendrogenesis, neurite growth, and synaptogenesis; the last two being mediated by the Netrin-1/DCC axis.


Towards a Better Understanding of Osteoclasts in Osteoporosis

Bone is, despite appearances, a very dynamic tissue. Bone structure is constantly remodeled, and a balance between the activities of osteoblasts that create bone extracellular matrix and osteoclasts that break down that matrix is necessary to maintain healthy, functional bones. With advancing age this balance is disrupted, shifting to favor osteoclast activity over osteoblast activity. Bones become weaker, less dense, and fragile, leading to osteoporosis and serious, life-limiting fracture events.

Given that osteoporosis is an imbalance, there are numerous possible approaches to the development of therapies. Identifying and removing the fundamental causes of reduced osteoblast activity or increased osteoclast activity would be the most likely to succeed. This means reversing or repairing the causative damage and dysfunction of aging. Chronic inflammatory signaling, such as that produced by senescent cells, is likely important, but there are many other contributing causes of aging that likely play a part in the disruption of bone tissue remodeling.

An alternative approach is compensatory: suppress osteoclast activity, or boost osteoblast activity. This is thought to be in principle easier, as any new discovery in the biology of these cells could lead to a therapy, but nonetheless present approaches have yet to produce sizable benefits by using small molecules to manipulate cell behavior. Even given a greater degree of success, compensation will always be less beneficial than addressing the underlying causes of osteoporosis, as those causes lead to many other aspects of aging.

Recent Advances in Osteoclast Biological Behavior

Osteoclasts, as an important component of the bone microenvironment, have always played an irreplaceable role in bone homeostasis. Abnormalities in osteoclast function can lead to abnormal bone resorption. If osteoclasts are hyperfunctional, they can cause degenerative bone diseases such as osteoporosis and osteoarthritis; if they are dysfunctional or declining, they can cause osteosclerosis. Drugs for bone-related diseases affect the process of bone resorption by osteoclasts in three main ways: differentiation, function, and apoptosis. Therefore, we summarize the biological characteristics of osteoclasts in terms of differentiation, apoptosis, behavior changes, and coupling signals with osteoblasts based on previous studies, in this review.

Although we have a more comprehensive understanding of osteoclasts, we still do not know the effects of various modulators on osteoclast behavior in the systemic as well as in the local environment and their mechanisms of action. Additionally, we still have a lot to learn about the processes that control osteoclast sexual dimorphic responses. Research of this phenomena are essential because they can shed light on the pathophysiology of metabolic bone disorders like osteoporosis and how individuals respond to treatment.

The identification of gene targets by understanding these mechanisms may lead to more effective treatments for metabolic diseases of the skeleton. As for coupling signals between osteoclast and osteoblast, rather than simply identifying potential coupling factors, it is time to move on to the next phase. It is imperative that we spend time understanding the kinds of mechanisms that drive the remodeling process, and identify the aspects of those mechanisms that can be used to intervene in human skeletal disorders. Furthermore, we think that interactions existing among macrophages, osteoclasts, and osteoblasts contribute to maintaining bone homeostasis. Therefore, we believe that pathological connections among these cells in disease states and their negative mechanisms will be a new field for further exploration.

The Relationship Between Sarcopenia and Cardiovascular Disease

Sarcopenia is the progressive loss of muscle mass and strength that takes place in later life. Both sarcopenia and cardiovascular disease are accelerated by the chronic inflammation of aging, but the onset of physical weakness resulting from sarcopenia can also contribute to cardiovascular disease via reduced physical activity. As this paper notes, other mechanisms may also be involved in the relationship between sarcopenia and cardiovascular disease. Muscle tissue is metabolically active, and the loss of that tissue has more consequences than just a decline into frailty.

With the advent of population aging, aging-related diseases have become a challenge for governments worldwide. Sarcopenia has defined as a clinical syndrome associated with age-related loss such as skeletal muscle mass, strength, function, and physical performance. It is commonly seen in elderly patients with chronic diseases. Changes in lean mass are common critical determinants in the pathophysiology and progression of cardiovascular diseases (CVDs). Sarcopenia may be one of the most important causes of poor physical function and decreased cardiopulmonary function in elderly patients with CVDs. Sarcopenia may induce CVDs through common pathogenic pathways such as malnutrition, physical inactivity, insulin resistance, inflammation; these mechanisms interact.

Sarcopenia and CVDs are highly prevalent in the elderly and share common pathogenesis and interactions. Understanding their relationship is still in its initial stages, and more clinical and experimental data are needed. A large number of studies have shown that the progression of CVDs and the decline in muscle function will further worsen the patient's condition. By screening patients for sarcopenia at an early stage, establishing effective early detection methods and evaluation methods, and providing early and comprehensive interventions, the progression of the disease can be effectively delayed. Nevertheless more importantly, patients with CVDs should be rehabilitated as soon as possible to break the vicious cycle of sarcopenia and CVDs through scientific nutritional programs and training guidance. Effective treatment of either sarcopenia or CVDs can have a positive impact on another disease.


A Popular Science Article on Approaches to Clearing Senescent Cells

The development of senolytic therapies, capable of selectively destroying senescent cells in old tissues, is a very promising area of medicine. When present even in comparatively small numbers, senescent cells actively maintain a disrupted, inflammatory state of tissues via their secretions. A dozen or more biotech companies are working senolytic therapies of various types. If anything, however, far too little work is taking place on the assessment of first generation senolytic drugs in humans, given that these treatments have produced impressive degrees of rapid rejuvenation in aged mice in many different studies. Those drugs are readily available at low cost, and can in principle be prescribed off-label by physicians.

Accumulation of senescent cells can occur due to diminished clearance ability of the immune system or persistent exposure to senescence-inducing stimuli that produce more cells than can be cleared in time. Such accumulation can lead to a chronic inflammatory state in the surrounding tissue microenvironment, also referred to as inflammaging, that further promotes senescence in neighboring healthy cells.

Due to the deleterious effects of cellular senescence, the senescent cell has been the target of active research to tackle age-related pathologies either through the approach of seno-rejuvenation or senolytics. In a pioneering study done in 2011, researchers showed that by removing p16Ink4a-positive senescent cells, there was observable delayed tissue dysfunction and extended healthspan in a progeroid mouse model.

Senolytics refers to a class of pharmacological agents that eliminate senescent cells by inducing apoptosis. Compared to their healthy counterparts, senescent cells are highly resistant to apoptosis even in the presence of cellular stresses due to activation of pro-survival and anti-apoptotic pathways. One of the most common senolytics approaches is to inhibit pro-survival pathways such as those regulated by the BCL-2 protein family and PI3K/AKT pathway. Beyond the use of senolytic drugs, there is also increasing interest in the use of engineered immune cells for senolytics purposes, stemming from the observation on the role of immune system to clear senescent cells. In a recent study, developed chimeric antigen receptor (CAR) T cells as senolytic agents to target cells expressing urokinase-type plasminogen activator receptor (uPAR).


Vascular Stiffness and Its Contribution to Age-Related Disease

The largest cause of human mortality is cardiovascular disease. Further, looking beyond all of the deaths clearly defined as a failure of the cardiovascular system - such as stroke, heart attack, heart failure, and so forth - it is the case that vascular aging contributes to the progressive dysfunction of organs throughout the body, and thus to death by many other causes. Narrowing of blood vessels due to atherosclerosis deprives energy-hungry tissues of the nutrients and oxygen that they need. Stiffness of blood vessel walls disrupts the finely balanced feedback mechanisms that govern blood pressure, giving rise to the chronically raised blood pressure of hypertension. Hypertension in turn causes pressure damage to delicate tissues throughout the body, accelerating the dysfunctions of aging. That "a man is as old as his arteries" is as true in spirit now as it was in the 1600s when Thomas Sydenham first said as much.

What can be done about vascular stiffening? Clearing senescent cells and reducing inflammatory signaling should help with some of the dynamic dysfunction in the smooth muscle responsible for contraction and relaxation of blood vessels. Finding ways to break persistent cross-links in the vascular extracellular matrix will also hopefully prove to be useful. The real challenge will be restoration of elastin and its relationship with collagen in the extracellular matrix, as elastin is largely only deposited during the developmental period of life. The structure of elastin is complex and the details of that complexity matter when it comes to the structural properties of tissue, such as elasticity. This likely means that sophisticated control over the cell populations capable of depositing elastin will be needed in order to rejuvenate the extracellular matrix in this way, and all too little work in that direction has been undertaken to date.

Vascular Stiffness in Aging and Disease

The mechanisms of increased stiffness in aging are both extracellular and cellular. The three main aortic wall components, elastin, collagen, and smooth muscle cells, vary along the length of the aortic tree. With aging, these components of the aortic wall are altered. The number of elastic fibers and smooth muscle cells in the tunica media decrease, while collagen fibers increase with advancing age. The number of smooth muscle cells in the tunica media decreases with age and vascular smooth muscle cell migration from the tunica media thickens the intima.

The most important mechanism studied as a cause of age-related increases in vascular stiffness is alteration in the extracellular matrix (ECM), resulting from an increase in collagen and decrease in elastin. The ECM is composed of a complex network of different matrix proteins, metalloproteases, and glycosaminoglycans, which are also responsible for the structural integrity of the vasculature, and therefore contribute to its stiffness. Collagen is a very stiff protein with the function of limiting vessel elasticity and distension, and is therefore fundamental to defining the stiffness of the arterial wall. Collagen deposition throughout the vasculature increases with age, which alters the normal ECM network. This has been shown to occur in the intima, media, and adventitia of the vessel wall leading to substantial changes in its morphology and function. In addition to increased collagen deposition, there is also increased non-enzymatic glycation. This is also responsible for age-related increases in arterial stiffness, as it induces collagen cross-linking, which increases stiffness.

Unlike collagen, elastin, the other major ECM protein, provides flexibility and extensibility of the vessel wall. Elastin fibers are mainly found in the medial layer of large elastic arteries and are oriented around smooth muscle cells and collagen. Degradation of elastin fibers with aging is mediated by the increases of proteolytic enzymes, e.g., matrix metalloproteases (MMP), which degrade elastin fibers, resulting in an increase in collagen/elastin ratio, which in turn increase vessel wall stiffness. Nevertheless, the extent to which increases in collagen and decreases in elastin contribute to increased vascular stiffness with aging remains controversial.

Calcification of the vessel wall occurs with normal aging, reducing the vessel wall's distensibility. In humans there is a direct correlation between aortic calcification and arterial stiffness. Calcinosis of arterial walls with aging has been associated with increased cholesterol content in the elderly, suggesting a relationship between these processes. However, it is unknown which process occurs first, although some have speculated that calcinosis increases interaction with cholesterol molecules in the arterial wall. Increases in oxidative stress that occur with aging, mainly due to decreases in mitophagy and autophagy, stimulate vascular calcification by activating several signaling cascades. One of the best studied signaling pathways involves the upregulation of bone morphogenetic proteins due to increases in oxidative stress, which results in increased vascular calcification.

The vascular endothelium is the innermost, monolayer of cells in blood vessels. When the endothelium is healthy, vascular tone is regulated by a balance of vasoconstriction and vasodilation; the latter controlled by nitric oxide (NO) release. Reduced bioavailability of nitric oxide leads to endothelial dysfunction, resulting in impaired vasodilation, which increases arterial stiffness. Endothelium impairment and decreased NO bioavailability occur with normal aging, ultimately leading to a proinflammatory, vasoconstrictive state, resulting in increased vascular fibrosis and arterial stiffness. Furthermore, endothelial dysfunction leads to an increase in oxidative stress through an increase in the production of superoxide causing damage to the vessels leading to changes in hemodynamics. Recently, it has also been proposed that autophagy, the cellular housekeeping mechanism that maintains cellular homeostasis, decreases in the aging endothelium, further leading to increases in oxidative stress. This was further confirmed with the use of a pro-autophagy treatment, which reduced arterial stiffness and oxidative stress in aged mice.

Vascular smooth muscle cells (VSMCs) have recently been discovered as important contributors to age-related increases in arterial stiffness. This increased VSMC stiffness is due to the direct relationship between VSMCs and endothelial cells. Endothelial cells regulate vascular tone mainly through the release of nitric oxide. This reduces active tone of VSMCs, which counteracts the increase in wall shear stress that occurs with both aging and high blood pressure. However, aging also leads to a decrease in the number of cells within the vascular wall due to a decrease in cell proliferation with age. Multiple mechanisms mediate the decrease of VSMCs with age, but most notably inflammation and calcification, which increase VSMC apoptosis. In humans, the VSMCs lost with aging are replaced by collagen fibers in the media of the arterial wall, resulting in increased vascular stiffness.

Lower Serum Klotho Correlates with Longer Sleep Duration in Older People

Higher levels of klotho slow aging in animal models, most likely largely a result of improved kidney function in later life. Klotho upregulation also slows cognitive aging, which may be downstream of effects on the kidneys, given the importance of kidney function to many organs. The correlation reported here between klotho and sleep duration is interesting enough to comment on, but it seems likely to be very indirect. Altered sleep duration with age is an emergent consequence of countless changes and dysfunctions. The path through mammalian biochemistry that leads from klotho to sleep is likely a winding one.

The sleep duration recommended by the National Sleep Foundation in 2015 was as follows: 7-9 hours in young people and adults, and 7-8 hours in elderly people. Excessive or insufficient sleep duration is disadvantageous for health. Previous studies have shown that sleep duration is associated with cardiovascular disease, cognitive decline, and metabolic syndrome, and aging.

Klotho protein is a multifunctional protein encoded by the klotho gene, and its expression level is associated with aging. It was found that mice lacking klotho suffer from premature aging syndrome, the lack of klotho in serum is also associated with heart aging, and decreased klotho levels are found in patients with various aging-related diseases, such as metabolic syndrome, cancer, and hypertension. In contrast, high level of klotho prolongs lifespan.

Aging is an inevitable process for human being, but the speed of aging is affected by many factors. Aging is affected by environmental, genetic, and epigenetic factors. On the other hand, the expression level of klotho may be potentially involved in the relationship between sleep duration and aging. Sleep disorders and aging are common public health problems, and the potential association between sleep duration and the anti-aging protein klotho is largely unexplored. Therefore, the purpose of this study was to investigate the potential association between them using the data of the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016. Our hypothesis is that sleep duration is associated with the serum anti-aging protein klotho concentration.

Sleep duration was non-linearly associated with the level of klotho protein in the serum, with a negative association between sleep duration and serum klotho concentration after adjusting for confounding variables. Serum klotho of the participants in the highest tertile (more than 7.5 hours) was 21.9 pg/mL lower than those in the lowest tertile (less than 5.5 hours). Thus our results revealed that people who sleep more than 7.5 hours per night have decreased levels of the anti-aging protein klotho in their serum, thus being more at risk of aging-related syndromes.


Epigenetic Age Acceleration Is Not Associated with Age-Related Macular Degeneration

Researchers here show that present epigenetic clocks perform poorly in the context of retinal aging and the dysfunction of age-related macular degeneration. Epigenetic age acceleration is the difference between epigenetic age as assessed by the clock algorithm and chronological age. In the more established clocks, a higher epigenetic age correlates with risk of mortality and many age-related conditions. It remains largely unknown as to how specific forms of age-related damage and dysfunction lead to specific epigenetic changes, however, and therefore poor performance in any given use case can only be discovered, not predicted in advance. This makes it a challenge to use epigenetic clocks in their most desired capacity, as a low-cost, fast alternative to life span studies in the assessment of potential rejuvenation therapies.

This is the first study to our knowledge formally evaluating whether epigenetic age acceleration (EAA) in Horvath-multi tissue, Hannum, and Skin and Blood epigenetic clocks is associated with age-related macular degeneration (AMD) and important risk factor covariates including smoking status. We sought to address whether EAA is observed in the retinal pigment epithelium (RPE), as it is a primary site of AMD pathogenesis, and in whole blood, as the epigenetic clocks have been widely applied and validated in blood-derived genomic DNA.

EAA was not observed in AMD. However, we observe positive EAA in blood of smokers, and in smokers with AMD. In the RPE, we observed a marked negative EAA across all groups with no significant differences in EAA between AMD and normal samples using all three clocks. This result cannot be characterised as true negative age acceleration because of poor performance of the epigenetic clocks in RPE. The consistent poor correlation of predicted DNAm age with chronological age observed in the RPE markedly improved when analysing whole blood-derived genomic DNA data, explained by the datasets used to train each respective epigenetic clock.

Reasonable performance of each respective epigenetic clock in whole blood strengthens the observation of no association of EAA with AMD in blood, though this remains open to further investigation in the RPE, which can be addressed using a bespoke RPE epigenetic clock with greater predictive accuracy. Construction of a tissue-specific RPE clock is necessary for future studies to capture the specific epigenetic ageing processes in the RPE.


Longevity.Technology Looks Back at 2021

A fair number of news and interest sites covering aging research and the development of therapies to treat aging as a medical condition have come and gone over the years. Longevity.Technology is one of the few that seems likely to stick around for a while, now that there is a growing longevity industry to cover, and thus the ability to bring in enough revenue in traditional ways to run a small professional journalism organization. The Longevity.Technology staff recently published a set of short retrospective articles, looking back on industry news from 2021; some are linked below.

The lie of the longevity landscape - 2021 into 2022

November saw leading lights from across the longevity sector come together in London to announce the formation of the Longevity Biotechnology Association (LBA). The non-profit organisation says it aims to represent those behind the development of "new medicines and therapies to prevent and cure, rather than merely manage, the health conditions of late life."

Kicking off in June, the On Deck Longevity Biotech Fellowship is on a mission to increase the number of people working to build longevity biotechnology companies. Nathan Cheng, ODLB's Program Director hopes the Fellowship will address the fact that as more and more capital flows into the antiaging biotechnology sector, the major obstacle to progress has become the lack of founders.

The National Institute on Aging, which is part of the National Institutes of Health, invited applications for longevity clinical trials to slow aging and prevent or treat age-related diseases in February of this year. Previously, the FDA has approved biotech interventions that address individual diseases, rather than tackling aging itself. However, this funding opportunity is available to researchers who want to treat multiple chronic conditions by modulating fundamental aging-related mechanisms. In short, those who want to target aging itself.

A blog on the landscape - an overview of the longevity space

The worlds of cryptocurrency, blockchain, and longevity have collided this year in several very interesting ways. VitaDAO's crypto auction raised 400% of expectation, gathering in over $5 million for longevity research, and the Longevity Science Foundation began to use blockchain technology in its funding selection process. 2021 also saw cryptocurrency HEX founder Richard Heart's creation of a new currency, Pulse. Prior to the launch of this new cryptocurrency, Heart made headlines with an airdrop, in which he gave away some Pulse to those who donated to the SENS Research Foundation (SRF) during a specific 'sacrifice' window.

Seeking to cut the Gordianesque knot of red tape, the Longevity Impetus Grants launched this year, with the aim of speeding up research that slows down aging. Seeking to have a broad impact on the longevity field, the grants will support projects that challenge assumptions, develop new tools and methodologies, discover new ways to reverse aging processes, and/or synthesise isolated manifestations of aging into a systemic perspective. With $26 million to give away (including 1500 Ethereum from Vitalik Buterin), grants will be $10k-500k, with decisions made in three weeks.

2021 in longevity - prolific terrific scientifics

Recent events have, of course, thrown a spotlight on our immune systems, but several stories this year have focused on our immune systems for other reasons. In May, we reported how scientists are leveraging the power of immune cells to clear the body of senescent cells that contribute to aging and many chronic diseases in the hope that this new understanding may open the door to new ways of treating age-related chronic diseases with immunotherapy. Senotherapeutic therapies are one way to remove senescent cells, but if our body's own natural surveillance system could be stimulated to do the job, it could be a way to tackle senescence without side effects.

In July, the Buck Institute for Research on Aging announced an aging clock for immunosenescence. An inflammatory clock of aging (iAge) - it measures inflammatory load, rather than causing controversy - predicts multi-morbidity, frailty, immune health, cardiovascular aging and is also associated with exceptional longevity in centenarians.

Interviews of 2021: senescence, young blood and dog longevity

With much of the world focused on the potential of young blood to improve longevity, our interview with UC Berkeley professor Irina Conboy challenged that view. She's well-qualified to do so, having worked in the lab that produced the seminal 2005 paper on heterochronic parabiosis reversing aging in mice. "We think that if you inject an old person with bodily fluids from a young person, nothing good will happen, unless there is a critical blood loss and a need for a transfusion. But if you can neutralise or remove some determinant proteins that are elevated in ways that become counterproductive, then that old person will become younger."

Targeting senescent cells (old cells that don't die off and build up in our bodies as we age) continued to be a hot topic in longevity this year - so much so, we even wrote a dedicated market report on it! But, with several companies now actively developing senolytic therapeutics that target and kill senescent cells, we spoke to Buck Institute professor Judith Campisi, one of the world's leading authorities on senescence, to get her perspective. "The first question we want to know is, are these different cell populations good or bad, or both? We just don't know. We definitely want senolytics that hit the bad guys, and not the good guys - and we don't have that yet. We don't have that at all."

Interviews of 2021: spermidine, placentas and clinical trial lessons

When it comes to the study of aging, the Buck Institute in California is synonymous with some of the most cutting edge research in the field. This year, the Buck also came to our attention on the commercial side of longevity, with three of its top researchers joining forces to start a company called Gerostate Alpha. Our two-part interview covered the formation of the company, and its goal to discover "interventions that attenuate or halt multiple aging indications simultaneously." Gerostate sets itself apart from many other companies in the field by not focusing on a particular pathway, and concentrating instead on compounds that extend lifespan in mice.

A lot of companies we spoke to over the past 12 months were particularly interested in mitochondria's role in longevity. These miniature organs within our cells play a key role in providing the energy needed for growth, repair, and rejuvenation, and their decline as we age is linked to a range of age-related diseases. US biotech Cohbar has been working in this field longer than most, and our interview with the company's CEO shed some light on the progress made to date, including the discovery of key peptides.

Senescent Astrocytes May Negatively Affect the Function of Neurons

A good deal of evidence points towards cellular senescence in the supporting cells of the brain, such as astrocytes and microglia, as an important contribution to neurodegeneration, cognitive decline, and dementia. Senescent cells behave abnormally and secrete a potent mix of pro-growth, pro-inflammatory signals that are known to degrade structure and function in many different organs. Chronic inflammation in brain tissue is strongly implicated in the onset and progression of neurodegenerative conditions, and clearance of senescent cells in the brain via senolytic therapies has been shown to reverse pathology in animal models of neurodegeneration.

The decline in brain function during aging is one of the most critical health problems nowadays. Although senescent astrocytes have been found in old-age brains and neurodegenerative diseases, their impact on the function of other cerebral cell types is unknown. The aim of this study was to evaluate the effect of senescent astrocytes on the mitochondrial function of a neuron.

In order to evaluate neuronal susceptibility to a long and constant senescence-associated secretory phenotype (SASP) exposure, we developed a model by using cellular cocultures in transwell plates. Rat primary cortical astrocytes were seeded in transwell inserts and induced to premature senescence with hydrogen peroxide - stress-induced premature senescence (SIPS). Independently, primary rat cortical neurons were seeded at the bottom of transwells. After neuronal 6 days in vitro (DIV), the inserts with SIPS-astrocytes were placed in the chamber and cocultured with neurons for 6 more days. The neuronal viability, the redox state, represented by reduced glutathione/oxidized glutathione (GSH/GSSG), the mitochondrial morphology, and the proteins and membrane potential were determined.

Our results showed that the neuronal mitochondria functionality was altered after being cocultured with senescent astrocytes. In vivo, we found that old animals had diminished mitochondrial oxidative phosphorylation (OXPHOS) proteins, redox state, and senescence markers as compared to young rats, suggesting effects of the senescent astrocytes similar to the ones we observed in vitro. Overall, these results indicate that the microenvironment generated by senescent astrocytes can affect neuronal mitochondria and physiology.


Sucrase-Isomaltase Deficiency as a Health-Inducing Mutation

Researchers here note that the uncommon sucrase-isomaltase deficiency found in some Greenland populations may be generally beneficial to long-term health in adults, removing many of the downsides to ingesting sucrose. Humans did not evolve in a sugar-rich environment, and we are poorly adapted to the consequences of the high sugar intake that characterizes wealthier populations. An identified and useful mutation in a human population can be the first step on the road to a therapy that can improve health, and perhaps that will happen here.

Researchers analysed data from 6,551 adult Greenlanders and conducted experiments on mice. The results demonstrate that carriers of the genetic variation have what is known as sucrase-isomaltase deficiency, meaning that they have a peculiar way of metabolizing sugar in the intestine. Simply put, they do not absorb ordinary sugar in the bloodstream the way people without the genetic variation do. Instead, sugar heads directly into their intestine.

"Gut bacteria convert the sugar into a short-chain fatty acid called acetate, which in previous studies has been shown to reduce appetite, increase metabolism, and boost the immune system. That is most likely the mechanism happening here. Adult Greenlanders with the genetic variation have lower BMI, weight, fat percentage, and cholesterol levels, and are generally significantly healthier. They have less belly fat and might find it easier to get a six pack. It is amazing and surprising that a genetic variation has such a profoundly beneficial effect."

While the variation has clear health benefits for adult Greenlanders, it is problematic for their children. "Younger carriers of the variation experience negative consequences due to their different type of sugar absorption. For them, consuming sugar causes diarrhea, abdominal pain and bloating. Our guess is that as they age, their gut bacteria gradually get used to sugar and learn how to convert it into energy." The research team hope that they can use the results of their new study to lay the groundwork for developing new drugs that might one day be used to treat cardiovascular disease and obesity.