Today is Giving Tuesday: if you Favor a Long, Healthy Life for Everyone, then Make a Donation to Support the Work of the SENS Research Foundation
Following the commercial shopping days of Black Friday and Cyber Monday is the day for non-profits and charitable donation, Giving Tuesday. It is a young idea, first announced in 2012, but a great idea, and one that has seen considerable adoption. Of this cluster of marked days, I expect Giving Tuesday to be the cultural phenomenon that will produce the greatest long-term change for the better. Just focusing on support for medical research, it is clear that very few people put any thought into where therapies come from and how progress in medicine happens. Every opportunity to explain to the public at large that the most important early stages of medical research are largely funded by philanthropy is an opportunity to increase that funding and speed progress. Yes, most people will ignore the request for help, but every year the communities focused on research for specific diseases grow. Every year more people realize that we live in the midst of a revolution in biotechnology, and medicine can and will make enormous progress in the decades ahead. In our case the disease is aging: addressing the root causes of aging will, to the extent that it is comprehensive and effective, halt and turn back all of the hundreds of named forms of age-related disease, as well as the frailty and degeneration that is currently thought of as normal.
For Giving Tuesday 2016 I ask you to make a donation to the SENS Research Foundation or Methuselah Foundation, organizations that have done more than any other over the past fifteen years to advance the state of rejuvenation research. They have pushed the scientific community towards developing much more of the basis for therapies capable of repairing the cell and tissue damage that causes aging, and funded many of these programs. They have removed roadblocks and enabled other groups to make significant progress. Indeed, the entire culture of the scientific community has changed over that time, from one in which it was career-threatening to talk about extending human life spans to one in which many researchers talk openly and publish papers on this topic. Now the biggest argument is over how to proceed. That, again, has a lot to do with the years of advocacy carried out by the SENS Research Foundation, Methuselah Foundation, and their allies. Fifteen years ago, next to no work on repair of the causes of aging was taking place. Now there is at least some funded research in every important line of work, and some are well funded indeed. This has come to pass because over this time a great many people have made charitable donations to the SENS Research Foundation and Methuselah Foundation, and those organizations made very good use of that money.
Until the end of 2016, all single donations made to the SENS Research Foundation will be matched, dollar for dollar, by the generosity of Michael Greve, who has put up a $150,000 challenge fund. Similarly, Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! have put up another $36,000 challenge fund that will match the next year of donations for anyone who signs up as a SENS Patron to make monthly donations to the SENS Research Foundation. What are you waiting for?
This is a great time for progress in rejuvenation research and development, and a great time to reinforce that progress. The first class of therapies based on the SENS vision for rejuvenation, clearance of senescent cells, is in active development by a number of startup companies, including Oisin Biotechnologies, seed funded by the Methuselah Foundation and SENS Research Foundation, and UNITY Biotechnology, where the principals have raised more than $100 million to date to bring this therapy to the clinic. Other types of rejuvenation therapy that address other forms of cell and tissue damage are within a few years of that tipping point, given sufficient funding for continued research. Researchers focused on breaking down the cross-links that cause arterial stiffness and loss of elasticity in other tissues have made great strides in building the necessary tools thanks to SENS Research Foundation funding, and are presently engaged in the search for drug candidates. Removal of the amyloids that build up in old tissues is showing progress also in recent years, with a successful trial of clearance of transthyretin amyloid and the first trial in which amyloid- was cleared in Alzheimer’s disease patients. There is much more to tell, but you get the picture. Things are moving, the wheel is turning, and this is in large part due to our support for the SENS Research Foundation and Methuselah Foundation in past years.
We, the everyday philanthropists who dare to dream big, have helped to make these successes possible. We have pushing things past the first, hardest part of the bootstrapping process, and brought the end to frailty and disease in aging that much closer. We light the way, by our participation and advocacy attracting those who are more wealthy and conservative in their donations, and who were waiting for signs of support before stepping in. By donating today to the SENS Research Foundation and Methuselah Foundation, you help to set the foundation for the successes of the 2020s, for the widespread clinical availability rejuvenation therapies that, given the funding, will come to pass in that decade.
Rates of obesity and high blood pressure, or hypertension, follow the increases in wealth and comfort that have spread through much of the world over the past 60 years. Regions that are in the process of transitioning from predominantly poor agricultural populations to a level of wealth and mix of occupations that looks much more like Europe or the US, with South Korea as a good example of the full span of such a transition, see rising life expectancy as well as a rising level of lifestyle conditions. High blood pressure drives the development of cardiovascular disease, and is made worse by excess fat tissue and lack of exercise. Though at present we can’t do much about the root cause of age-related increases in blood pressure, which is loss of elasticity in blood vessels, other than fund the most promising research that offers a path to meaningful therapies, we can adopt lifestyle choices that avoid making the problem larger than it has to be. Further, the past 20 years have seen some surprisingly effective advances in controlling high blood pressure through medication, surprising since these results have been achieved without doing much to address the underlying causes, but the very widespread use of these therapies has yet to spread to some of the regions that are now seeing increased incidence of hypertension.
In the past 40 years, there has been a large increase in the number of people living with high blood pressure worldwide because of population growth and ageing – rising from 594 million in 1975 to over 1.1 billion in 2015. The largest rise in the prevalence of adults with high blood pressure has been in low- and middle-income countries (LMICs) in south Asia (eg, Bangladesh and Nepal) and sub-Saharan Africa (eg, Ethiopia and Malawi). But high-income countries (eg, Australia, Canada, Germany, Sweden, and Japan) have made impressive reductions in the prevalence of adults with high blood pressure, according to the most comprehensive analysis of worldwide trends in blood pressure to date.
Both elevated systolic (higher than 140 mmHg; first number in blood pressure reading) and diastolic (higher than 90mmHg) blood pressure can be used to make a diagnosis of high blood pressure. Recent research suggests that the risk of death from ischemic heart disease and stroke doubles with every 20 mmHg systolic or 10 mmHg diastolic increase in middle and older ages. Over the past four decades, the highest average blood pressure levels have shifted from high-income western countries (eg, Norway, Germany, Belgium, France) and Asia-Pacific countries (eg, Japan) to LMICs in sub-Saharan Africa, South Asia, and some Pacific island countries. High blood pressure remains a serious health problem in central and eastern Europe (eg, Slovenia, Lithuania). The findings come from a comprehensive new analysis of global, regional, and national trends in adult (aged 18 and older) blood pressure between 1975 and 2015. This includes trends in average systolic (the maximum pressure the heart exerts while beating) and diastolic blood pressure (amount of pressure in the arteries between beats), as well as prevalence of high blood pressure. The Non-Communicable Disease (NCD) Risk Factor Collaboration pooled data from 1479 population-based studies totalling 19.1 million men and women aged 18 years or older from 200 countries (covering more than 97% of the world’s adult population in 2015).
“High blood pressure is the leading risk factor for stroke and heart disease, and kills around 7.5 million people worldwide every year. Most of these deaths are experienced in the developing world. Taken globally, high blood pressure is no longer a problem of the Western world or wealthy countries. It is a problem of the world’s poorest countries and people. Our results show that substantial reductions in blood pressure and prevalence are possible, as seen in high-income countries over the past 40 years. They also reveal that WHO’s target of reducing the prevalence of high blood pressure by 25% by 2025 is unlikely to be achieved without effective policies that allow the poorest countries and people to have healthier diets – particularly reducing salt intake and making fruit and vegetables affordable – as well as improving detection and treatment with blood pressure lowering drugs.”
Researchers here investigate a class of drug that blocks interleukin-1 receptor activity, something that has been found to reduce cell death and improve regeneration following stroke. This form of interference in cellular metabolism lowers the level of inflammation, but that may or may not be the most important mechanism in the outcome for stroke patients; it is plausible, but the details remain to be determined conclusively at this point.
The pro-inflammatory cytokine interleukin-1 (IL-1) is a major driver of inflammation, with well documented detrimental effects in multiple preclinical models of systemic inflammatory disease as well as in cerebral ischemia. To this end, the selective, naturally occurring competitive inhibitor of IL-1, interleukin-1 receptor antagonist (IL-1Ra) has shown potential as a new treatment for stroke. More specifically, in a number of experimental stroke paradigms IL-1Ra reduces infarct volume and improves long term functional outcome, including in co-morbid animals. However, exact mechanisms by which IL-1Ra is neuroprotective are yet to be fully established.
While much research has focused on limiting ischemic damage in the initial stages of acute reperfusion, it is also important to understand mechanisms that underpin brain repair following injury and develop strategies that enhance reparative endogenous processes, including adult neurogenesis. Ischemic injury elicits a robust neurogenic response by stimulating production of neuronal progenitor cells (NPCs) in distinct neurogenic regions, which include the subventricular zone (SVZ) and the subgranular zone (SGZ), to generate new functional neurons. Though mechanisms underlying post-stroke neurogenesis and the influence of inflammation on these processes are still poorly understood, it has been observed in young and aged animals that inflammation impairs both basal levels of neurogenesis and attenuates the neurogenic response triggered by central nervous system (CNS) injury via induction of the pro-inflammatory cytokines. IL-1, for example, reduces the proliferation and differentiation of NPCs to neurons in pathologies such as stress and depression, effects reversed by administration of IL-1Ra.
Here, we explored how inhibition of IL-1 actions by clinically relevant, delayed administration of subcutaneous IL-1Ra affects stroke outcome and neurogenesis up to 28 days after experimental ischemia, in aged/co-morbid and young rats. All experiments were performed using 13-month-old male, lean and corpulent (Cp) rats and 2-month-old Wistar rats. Cp rats are homozygous for the autosomal recessive cp gene (cp/cp), and spontaneously develop obesity, hyperlipidemia, insulin resistance, glomerular sclerosis, and atherosclerosis. Delayed IL-1Ra administration at 3 and 6 hours reperfusion in aged lean, aged Cp and young Wistar rats induced a significant reduction in infarct volume at 24 hours and 7 days of reperfusion, and a significant reduction in cortex loss at 28d in young Wistar rats. Reductions in infarct volume at 24 hours of reperfusion were 37%, 42% and 40% in aged lean, aged Cp and young Wistar rats respectively. IgG staining at 7 days reperfusion revealed a reduction of 40%, 48% and 46% in blood-brain barrier (BBB) damage in IL-1Ra treated aged lean, aged Cp and young Wistar animals respectively, versus their placebo-treated counterparts. A reduction of 26% was also observed at 14d reperfusion in young Wistar rats treated with IL-1Ra versus their placebo counterparts.
Our findings demonstrate that subcutaneous administration of IL-1Ra is neuroprotective in young and aged animals with multiple risk factors for stroke and increases post-stroke neurogenesis. It has previously been observed that delayed administration of IL-1Ra exerts neuroprotective effects at acute time points following experimental ischemia. Here we extend these findings to show that the early beneficial effects of IL-1Ra persist for at least 7 days in aged/co-morbid animals and for 28 days in young/healthy animals. Our data show that although 13-month-old corpulent rats had a plethora of stroke associated co-morbidities, infarct volumes were of a similar size to aged leans, suggesting that the extent of ischemic damage was close to maximal and that no further increase was possible. Conversely, younger rats were more resistant. This suggests that age is the primary variable that increases the brain susceptibility to infarction following an ischemic stroke. However, despite reaching maximal levels of infarction, tissue is still salvageable under these circumstances if IL-1Ra is administered within a therapeutic window.
Furthermore, our results indicate that although the delayed administration of IL-1Ra (3 and 6 hours from reperfusion onset) reduces infarct volume, it produces an increase on cellular proliferation and migration of immature neurons versus placebo counterparts in the SVZ following stroke in young and aged/co-morbid rats, suggesting that a reduced inflammation of the tissue fosters a more efficient repair of the damaged tissue. We also show that IL-1Ra increases the number of new integrated neurons in areas surrounding the infarct lesion in young animals compared to placebo groups a result that correlates with improvements in motor and behavioral sub-acute outcomes. The benefits of IL-1Ra are therefore not limited to inducing neuroprotection, but also favor and promote neurorepair mechanisms. We conclude that further studies are required to fully elucidate the mechanisms through which IL-1Ra may be mediating its beneficial, neurogenic effects.
In the paper I’ll point out today, researchers map an efficient form of protein quality control from stem cells and recreate it in somatic cells, producing extended life in nematode worms as a result. Proteins are large, complex molecules, and their correct function depends on the assumption of a precise three-dimensional arrangement after creation, a process known as protein folding. Proteins can and do misfold, however, and in doing so many become actively harmful rather than merely unwanted clutter. A baroque system of chaperone proteins assists in correct folding, as well as identification and removal of misfolded molecules. The presence of misfolded proteins is effectively a form of damage: some of the molecular waste that accumulates with age and contributes to the development of age-related disease consists of misfolded proteins, such as the various forms of amyloid, for example. The gradual failure of cellular recycling systems, such as declining lysosomal function caused by the presence of metabolic waste that is hard for the body to break down, or similar failures in the proteasome, also contribute to rising levels of damaged and dysfunctional proteins. Since aging is nothing more than the accumulation of damage and the reactions to that damage, more efficient operation of chaperone and other quality control systems in cells should slow aging: the less damage there is at any one time, the less of an opportunity that damage has to spread and cause secondary issues. It is probably not a coincidence that increased quality control activity is observed in many of the methods shown to modestly slow aging in laboratory animals, and that some forms of slowing aging cannot work without that quality control boost.
As for any study that extends life in short-lived species in this way, it is worth noting that the life span of short-lived species is far more plastic than that of longer-lived species such as we humans. Where the research community can directly compare methods, such as calorie restriction, exercise, or growth hormone receptor mutation, it is clear that doubling worm life spans or a 40-60% increase in mouse life spans certainly doesn’t map to that much of a change in human life span – or even more than just a few years. If it did, we’ve have noticed by now, as it would leap out of the data on human health and mortality. That researchers don’t see that in the data constrains the effects to be fairly small, a handful of years at most. So for my part I believe we should look at this and other similar studies as indicators of importance, not a literal guide to building human therapies. These studies help to point out which forms of age-related molecular damage have the biggest impact, and thus are the highest priority for repair via the methods outlined in the SENS rejuvenation research proposals. It isn’t a suggestion to attempt to adopt modified chaperone systems in humans, as that would be a highly inefficient way to proceed. It would likely produce results on a par with exercise or calorie restriction: improved health, modestly slowed aging. That is far less useful than methods of repairing the damage, clearing out all of the misfolded proteins every now and again before they rise to the level of causing real issues. Periodic repair can create rejuvenation if comprehensive enough. In the near term of decades, adjusting biology to run in a different way can only modestly slow aging; it will be a long time indeed before the research community is capable of safely creating a new biology that doesn’t age in this way. That is time far better spent on the faster path to working rejuvenation treatments.
Defining immortality of stem cells to identify novel anti-aging mechanisms
With age, somatic cells such as neurons lose their ability to maintain the quality of their protein content. Pluripotent stem cells, on the contrary, do not age and have increased mechanism to maintain the integrity of their proteins. The survival of an organism is linked to its ability to maintain the quality of the cellular proteins. A group of proteins called chaperones facilitate the folding of proteins and are essential to regulating the quality of the cellular protein content. This ability declines during the aging process, inducing the accumulation of damaged and misfolded proteins that can lead to cell death or malfunction. Several neurodegenerative age-related disorders such as Alzheimer’s, Parkinson’s or Huntington’s disease are linked to a decline in protein quality control.
Human pluripotent stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity necessarily demands avoidance of any imbalance in the integrity of their protein content. “There is one chaperone system, the TRiC/CCT-complex that is responsible for folding about 10% of all the cellular proteins. By studying how pluripotent stem cells maintain the quality of their proteome, we found that this complex is regulated by the subunit CCT8. Then, we discovered a way to increase the assembly and activity of the TRiC/CCT complex in somatic tissues by modulating this single subunit, CCT8. The increase resulted in prolonged lifespan and delay of age-related diseases of the model organism Caenorhabditis elegans. For this study we combined the results from human pluripotent stem cells and C. elegans, to have both in vitro and in vivo models, providing a more convincing approach. Our results show that expressing CCT8 as the key subunit of the complex is sufficient to boost the assembly of the whole system. It is very interesting that expressing this single subunit is enough to enhance protein quality and extend longevity, even in older animals. One of our next steps will be to test our findings in mice.”
Somatic increase of CCT8 mimics proteostasis of human pluripotent stem cells and extends C. elegans lifespan
Human embryonic stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity may demand avoidance of any imbalance in protein homeostasis (proteostasis) that would otherwise compromise stem cell identity. Here we show that human pluripotent stem cells exhibit enhanced assembly of the TRiC/CCT complex, a chaperonin that facilitates the folding of 10% of the proteome. We find that ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly. Moreover, increased TRiC/CCT complex is required to avoid aggregation of mutant Huntingtin protein. We further show that increased expression of CCT8 in somatic tissues extends Caenorhabditis elegans lifespan in a TRiC/CCT-dependent manner. Ectopic expression of CCT8 also ameliorates the age-associated demise of proteostasis and corrects proteostatic deficiencies in worm models of Huntington’s disease. Our results suggest proteostasis is a common principle that links organismal longevity with hESC immortality.
The comparative biology of aging and longevity, comparing the biochemistry of similar species with different life spans, is a good way to improve understanding of which aspects of our biology are important determinants of degeneration and age-related disease. In the open access paper linked here, researchers undertake an examination of gene expression profiles in cell cultures for a range of mammalian species, for example. Despite the usefulness, as an investigative method this will, I expect, be overtaken by prototype rejuvenation therapies based on damage repair in the years ahead. Aging is an accumulation of cell and tissue damage, and the best way to determine the contribution of any one particular type of damage is to remove it. Researchers are beginning that process for cellular senescence, now that senescent cells can be selectively destroyed in an efficient manner, and other items from the SENS portfolio of rejuvenation biotechnologies will be added as they reach the stage of practical demonstration in animal studies.
The maximum lifespan of mammalian species differs by more than 100-fold, ranging from ~2 years in shrews to more than 200 years in bowhead whales. While it has long been observed that maximum lifespan tends to correlate positively with body mass and time to maturity, but negatively with growth rate, mass-specific metabolic rate, and number of offspring, the underlying molecular basis is only starting to be understood. One way to study the control of longevity is to identify the genes, pathways, and interventions capable of extending lifespan or delaying aging phenotypes in experimental animals. Studies using model organisms have uncovered several important conditions, such as knockout of insulin-like growth factor 1 (IGF-1) receptor, inhibition of mechanistic target of rapamycin (mTOR), mutation in growth hormone (GH) receptor, ablation of anterior pituitary (e.g. Snell dwarf mice), augmentation of proteins of the sirtuin family, and restriction of dietary intake. While many of these genes and pathways have been verified in yeast, flies, worms, and mice, the comparisons largely involve treatment and control groups of the same species, and the extent to which they explain the longevity variations across different species is unclear. For example, do the long-lived species have metabolic profiles resembling calorie restriction? Do they suppress IGF-1 or growth hormone signaling compared with the shorter-lived species? More generally, how do the evolutionary strategies of longevity relate to the experimental strategies that extend lifespan in model organisms?
To address these questions, a popular approach has been to compare exceptionally long-lived species with closely related species of common lifespan and identify the features associated with exceptional longevity. Examples include the amino acid changes in Uncoupling Protein 1 (UCP1) and production of high-molecular-mass hyaluronan in the naked mole rat; unique sequence changes in IGF1 and GH receptors in Brandt’s bat; gene gain and loss associated with DNA repair, cell-cycle regulation, and cancer, as well as alteration in insulin signaling in the bowhead whale; and duplication of the p53 gene in elephants. Again, it is important to ascertain whether these mechanisms are unique characteristics of specific exceptionally long-lived species, or whether they can also help account for the general lifespan variation.
An extension of this approach has been cross-species analyses in a larger scale. For example, several biochemical studies across multiple mammalian and bird species identified some features correlating with species lifespan. Longevity of fibroblasts and erythrocytes in vitro, poly (ADP-ribose) polymerase activity, and rate of DNA repair were found to be positively correlated with longevity, whereas mitochondrial membrane and liver fatty acid peroxidizability index, rate of telomere shortening, and oxidative damage to DNA and mitochondrial DNA showed negative correlation. The advent of high throughput RNA sequencing (RNAseq) and mass spectrometry technologies has enabled the quantification of whole transcriptomes, metabolomes, and ionomes, across multiple species and organs. These studies revealed the complex transcriptomic and metabolic landscape across different organs and species, as well as some overlaps with the changes observed in the long-lived mutants created in laboratory.
While molecular profiling of mammals at the level of tissues may better represent the underlying biology, profiling in cell culture represents more defined experimental conditions and allows further manipulation to alter the identified molecular phenotypes. In this study, we examined the transcriptomes and metabolomes of primary skin fibroblasts across 16 species of mammals, to identify the molecular patterns associated with species longevity. We report that the genes involved in DNA repair and glucose metabolism were up-regulated in the longer-lived species, whereas proteolysis and protein translocation activities were suppressed. The longer-lived species also had lower levels of lysophosphatidylcholine and lysophosphatidylethanolamine and higher levels of amino acids; and the latter finding was validated in an independent dataset of bird and primate fibroblasts.
To what degree does regular exercise beyond the recommended minimum of 30 minutes a day improve long-term health and life expectancy? This and related questions on the shape of the dose-response curve for aerobic exercise remain open for debate. It is clear that being sedentary has a cost in terms of health and life expectancy, and the balance of evidence to date suggests that the 80/20 point for benefits due to exercise is found somewhere higher than the generally recommended level. Yet it is unclear as to whether professional athletes, who tend to live longer than the general population, live longer because of the high levels of exercise or because they also tend to be more robust individuals who would have enjoyed greater longevity regardless of profession. While it remains to put good numbers to much of the dose-response curve for exercise, this study of the Hadza people adds to the evidence for additional benefits to accrue to those who go beyond 30 minutes a day:
The Hadza live a very different kind of lifestyle – and a very active one, engaging in significantly more physical activity than what is recommended by U.S. government standards. They also have extremely low risk of cardiovascular disease. Researchers have spent several years studying the lifestyle of the Hadza. “Our overall research program is trying to understand why physical activity and exercise improve health today, and one arm of that research program aims to reconstruct what physical activity patterns were like during the evolution of our physiology. The overarching hypothesis is that our bodies evolved within a highly active context, and that explains why physical activity seems to improve physiological health today.”
The U.S. Department of Health and Human Services recommends that people engage in 150 minutes per week of moderate intensity activity – about 30 minutes a day, five times a week – or about 75 minutes per week of vigorous intensity activity, or an equivalent combination of the two. However, few Americans achieve those levels. The Hadza, on the other hand, meet those weekly recommendations in a mere two days, engaging in about 75 minutes per day of moderate-to-vigorous physical activity, or MVPA. Furthermore, and consistent with the literature identifying aerobic activity as a key element necessary to a healthy lifestyle, researchers’ health screenings of Hadza people have shown that the population has extremely low risk for heart disease. “They have very low levels of hypertension. In the U.S., the majority of our population over the age of 60 has hypertension. In the Hadza, it’s 20 to 25 percent, and in terms of blood lipid levels, there’s virtually no evidence that the Hadza people have any kind of blood lipid levels that would put them at risk for cardiovascular disease.”
While physical activity may not be entirely responsible for the low risk levels – diet and other factors may also play a role – exercise does seem to be important, which is significant because humans’ physical activity levels have drastically declined as we have transitioned from hunting and gathering to farming to the Industrial Revolution to where we are today. “Over the last couple of centuries, we’ve become more and more sedentary, and the big shift seems to have occurred in the middle of the last century, when people’s work lives became more sedentary. In the U.S., we tend to see big drop-offs in physical activity levels when people age. In the Hadza, we don’t see that. We see pretty static physical activity levels with age. This gives us a window into what physical activity levels were we like for quite a while during our evolutionary history, and, not surprisingly, it’s more than we do now. Perhaps surprisingly, it’s a whole lot more than we do now. Going forward, this helps us model the types of physical activity we want to be looking at when we explore our physiological evolution. When we ask what kinds of physical activity levels would have driven the evolution of our cardiovascular system and the evolution of our neurobiology and our musculoskeletal system, the answer is not likely 30 minutes a day of walking on a treadmill. It’s more like 75-plus minutes a day.”
Cellular senescence is one of the root causes of aging, and there are at present serious, well-funded efforts underway to produce rejuvenation therapies based on the selective destruction of senescent cells in old tissues. This progress is welcome, but it could have started a long time ago. It has taken many years of advocacy and the shoestring production of technology demonstrations to finally convince the broader community of scientists and funding institutions that the evidence has long merited serious investment in treatments to clear senescent cells. This is what it is, and now we must look to the future, for all that it has been a long, uphill battle. Cellular senescence is today having its time in the sun. Many research groups are linking the mechanisms of senescence to other aspects of aging; senescent cells are showing up in many more research papers than in past years, now that there is more of a scientific and financial incentive to search carefully for their influence. I think that declaring cellular senescence to be the causal nexus of aging, as one research group did, is going overboard a little, as there are, after all, other independent causes of aging, forms of metabolic waste and damage that would cause death and disease even if cellular senescence did not exist. Nonetheless, it is gratify to watch the spreading realization that cellular senescence plays a role in many areas of health and biology associated with aging. The advent of therapies that can remove senescent cells promises to produce sweeping beneficial effects on aging and disease.
There is a set of fairly well established threads of research that link aging with visceral fat tissue and immune dysfunction in the form of chronic inflammation. Visceral fat produces an accelerated pace of aging by generating greater chronic inflammation, producing an hostile tissue environment of inappropriate signals that attract immune cells and then cause those cells to become dysfunctional. The more fat there is the more inflammation it creates. This is thought to be the primary mechanism by which obesity increases the risk and severity of age-related disease. All of the common age-related diseases are accelerated in their progression by higher levels of chronic inflammation. The material difference between a lot of fat and a normal amount of fat is well demonstrated by a study in which researchers produced life extension in mice through surgical removal of visceral fat, but there is a mountain of data on human health to show that people who are overweight will suffer a shorter life expectancy and more age-related illness, and that this effect scales by the amount of excess fat tissue. How do senescent cells fit into this picture? One of the characteristic features of senescent cells is that they produce greater levels of chronic inflammation via the secretion of signal molecules such as cytokines. Of late, researchers have shown that senescent cells are found in the immune system, as in other cell populations. Given this, it should not be a surprise to find that cellular senescence can be implicated in the way in which visceral fat accelerates aging: their presence in visceral fat tissue and the immune cells interacting with that tissue fits right in with the broader picture of inflammation and bad cellular behavior.
Obesity accelerates T cell senescence in murine visceral adipose tissue
Visceral obesity is associated with chronic low-grade inflammation in visceral adipose tissue (VAT) and a sustained whole-body proinflammatory state, which may underlie metabolic and cardiovascular diseases. VAT inflammation associated with obesity involves a complex network of responses of immune cell components, including acquired immune cells such as various subsets of T cells and B cells and innate immune cells such as macrophages. Among these cells, CD4+ T cells have been recognized as a central regulator of chronic VAT inflammation. The number of CD4+ T cells in VAT increases as the tissue expands in obesity. Factors that drive CD4+ T cell expansion and into proinflammatory effectors in VAT during the development of high-fat diet-induced (HFD-induced) obesity may include MHC class II-associated antigens, possibly self-peptides, because the T cell receptor (TCR) repertoire of CD4+ T cells in VAT is limited, and deficiency of MHC class II protects mice from high fat diet (HFD)-induced VAT inflammation and insulin resistance. However, the obesity-associated immune background underlying chronic inflammation in VAT remains elusive.
Significant changes occur in the overall T cell populations with age. In CD4+ T cells, proportions of naive (CD44loCD62Lhi) cells sharply decline in ontogeny, with an age-dependent increase in cells of the memory phenotype (CD44hiCD62Llo). Among CD44hiCD4+ T cells, a unique population expressing programmed cell death 1 (PD-1) and CD153 actually increases with age in mice. The CD153+PD-1+CD44hiCD4+ T cell population shows compromised proliferation and regular T cell cytokine production on T cell receptor (TCR) stimulation but secretes large amounts of proinflammatory cytokines, such as osteopontin. These CD4+ T cells also show signatures of cell senescence, including a marked increase in senescence-related gene expression and nuclear heterochromatin foci, and are termed senescence-associated T cells (SA-T cells). Notably, the age-dependent development of SA-T cells, which may include autoreactive cells, is dependent on B cells. As such, the increase in SA-T cells is suggested to be involved in part in immune aging phenotypes such as impaired acquired immune capacity, increased proinflammatory traits, and high risk for autoimmunity.
In the present study, we demonstrate that CD153+PD-1+CD44hiCD4+ T cells are remarkably increased and preferentially accumulated in the VAT of HFD-fed mice in a B cell-dependent manner and that these CD4+ T cells show functional and genetic features strongly resembling SA-T cells that increase in secondary lymphoid tissues with age. We also indicate that the CD153+PD-1+CD44hiCD4+ T cells play a crucial role in inducing chronic VAT inflammation and metabolic disorder via secretion of large amounts of osteopontin. We demonstrated that adoptive transfer of CD153+PD-1+CD44hiCD4+ T cells, but not other CD4+ T cells, from HFD-fed spleens into VAT of ND-fed mice recapitulates the features of VAT inflammation, including a striking increase in CD11chiCD206lo macrophages and expression of proinflammatory cytokine genes. It is noteworthy that CD153+PD-1+CD4+ T cells in VAT of HFD-fed mice show features indistinguishable from those of CD153+ SA-T cells, which gradually increase systemically with age. The age-dependent increase in CD153+ SA-T cells may partly underlie the immune aging, including a reduction in acquired immunity and an increase in the inflammatory trait and autoimmunity risk. Obesity is also associated with diminished resistance against infection, chronic low-grade inflammation, and a greater susceptibility to autoimmunity. It has been suggested that the increase in CD153+ SA-T cells in chronological aging and systemic autoimmunity is attributable to a robust, homeostatic T cell proliferation, but the precise mechanism underlying the accumulation of these T cells in VAT of HFD-fed mice remains to be investigated. Nonetheless, it is an intriguing possibility that the predisposition often associated with obesity may partly be a systemic manifestation of the premature increase in CD153+ SA-T cells in VAT, since adipose tissues can constitute up to 50% to 60% of total BW in severe obesity.
Both birds and bats have great longevity for their size in comparison to mammalian species that do not fly, which has led researchers to theorize that the metabolic demands of flight lead to the evolution of cell structures that are more resistant to the damage of aging. Energy metabolism revolves around the mitochondria, the power plants of the cells, and so this in turn points to an important role for mitochondrial function and damage to mitochondria in determining aging and longevity, both across species and in individuals. There are good correlations between mitochondrial composition, the degree to which mitochondrial structures can resist oxidative damage, and mammalian life span, for example. Researchers here take a more reductionist approach to the question of why bats are exceptionally long-lived, and begin by mapping the RNA of a bat species:
Of all mammals, bats possess some of the most unique and peculiar adaptations that render them as excellent models to investigate the mechanisms of extended longevity and potentially halted senescence. They are considered the ‘Methusalehs’ among mammals due to their exceptional and surprising longevity given their body size and metabolic rate. Typically mammals that are small have a high metabolic rate (e.g. shrews) and do not live for a long time. However, despite their small size and high metabolic rate bats can live for an exceptionally long time, with the oldest recorded Brandt’s bat (wild caught as an adult) ever recaptured being more than 41 years old with a body weight of 7 grams. Indeed, to get a positive correlation between longevity and body size in mammals, bats must be removed from the analyses. By comparing the ratio of expected longevity to that predicted from the ‘non-bat placental mammal’ regression line (longevity quotient – LQ) only 19 species of mammals are longer lived than man, one of these species being the naked mole rat and the other 18 are bats. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity.
MicroRNA (miRNA) are a subset of short endogenous non-coding RNA that play a significant role in post-transcriptional regulation, via repression of translation. Since the first miRNA was discovered in 1993, a multitude of miRNA have subsequently been identified, and implicated in the regulation of the vast majority of biological pathways including cell cycle regulation, metabolism, tumorigenesis, as well as immune response. However, the role of miRNA regulation in mammalian ageing and the onset of age-related diseases has only recently been established. In mammals, various miRNA have been shown to be differentially expressed during ageing, most of which appear to be generally tissue-specific. In addition to tissue-specific ageing, it is increasingly evident that many miRNA regulate gene expressions in well-known ageing pathways, most notably in the p53 tumor suppressor pathway and insulin-like growth factor signaling pathway.
Despite being the second largest order of mammals (~1200 species), there is a scarcity of genomic and transcriptomic bat resources. To date, only five well-annotated bat genomes are publically available. Phylogenomic studies of bat genomes and other mammalian species reveal that a number of genes are under positive selection in bats. These genic adaptations have been correlated with traits such as echolocation, powered flight, hibernation, immunity and longevity. For example, specific non-synonymous mutations in GHR and IGF1R, key ageing-related genes, were detected in several long-lived vespertilionid bats (M. brandtii, M. lucifugus and Eptesicus fuscus), while a large proportion of genes involved in DNA repair (RAD50, KU80, MDM2, etc.) and the NF-B pathway (c-REL and ATM2, etc.) were reported to be under positive or divergent selection in M. davidii and P. alecto. These results suggest bats may better detect and repair DNA damage. Intriguingly, positive selection was also detected in mitochondrial-encoded and nuclear-encoded oxidative phosphorylation genes in bats, which may explain their efficient energy metabolism necessary for flight. Apart from comparative genome analysis, only a small number of transcriptomic studies on bats using have been carried out, focused primarily on the characteristics of hibernation, immunity, echolocation and phylogeny. However, the molecular mechanisms of adaptations affecting longevity are still far from understood, especially with respect to gene regulation.
In the present study, we sequenced six small RNA libraries from whole blood sampled from wild-caught greater mouse-eared bats (Myotis myotis) and for the first time made genome-wide comparisons of both miRNomes and mRNA transcriptomes between bat and non-bat mammalian species (human, pig and cow). The profiling of the M. myotis blood miRNome showed a large number of bat-specific miRNA involved in regulating important pathways related to immunity, tumorigenesis and ageing. Comparative analyses of both miRNomes and transcriptomes also revealed distinctive longevity mechanisms in bats. Several up-regulated miRNA possibly act as tumor suppressors. Gene Ontology (GO) enrichment analysis of differentially expressed protein-coding genes showed that up-regulated genes in bats compared to other mammals were mainly involved in mitotic cell cycle and DNA damage repair pathways while a high number of down-regulated genes were enriched in mitochondrial metabolism. The results and data presented here show unique regulatory mechanisms for protection against tumorigenesis, reduced oxidative stress, and robust DNA repair systems, likely contribute to the extraordinary longevity of bats.
Very few genetic variants robustly correlate with longevity across different study populations, and those that do, such as variants of APOE and FOXO3A, have small effects, only visible in the mortality statistics of large numbers of people. This indicates that the genetics of longevity, the way in which variations in metabolism and the response to high levels of age-related cell and tissue damage in later life can produce modestly different mortality rates, is a matter of many thousands of tiny, interacting contributions, very sensitive to environmental factors. It appears ever less likely that there will be any easy, small number of genetic changes that can be made to humans in order to produce significant lengthening of life. Thus the study of genetics and longevity isn’t the place to be looking for cost-effective ways to produce radical life extension of decades and more. This paper is one of many recent illustrations of this point; none of the described problems would be anywhere near as much of a challenge if there was a large genetic effect on aging and longevity with simple, narrow origins there to be found. That would stand out from the data much more readily.
The results of many genome-wide association studies (GWAS) of complex traits suffer from a lack of replication. Differences in population genetic structures among study populations are considered to be possible contributors to this problem. One aspect of population structure – the differences in genetic frequencies among subgroups of individuals comprising the population – was traditionally linked with the effects of population stratification. Another one – the presence of linkage disequilibrium (LD) in many parts of the human genome including those that contain causal single-nucleotide polymorphisms (SNPs) – was actively exploited in GWAS of complex traits. Methods of fine mapping following the “discovery” phase are used for evaluating causal SNPs. One could expect that the non-replication problem due to differences in LD patterns among study populations in GWAS would disappear if the detected marker SNP is a causal one, i.e., if it contributes to the variability of a trait. It turns out that the differences in LD levels around a functional SNP may still contribute to the non-replication problem.
The estimated associations in this case depend on whether the detected functional SNP is in LD with another functional SNP, the effects of these SNPs on the trait in the absence of LD (pure effects), and on the level of LD between corresponding SNP loci. This property has important consequences for interpretation of the results of genetic analyses of complex traits. In the presence of LD the estimated effects of a causal SNP may be spurious and may incorrectly characterize the biological relationships between the SNP and the trait. In contrast the pure effect of a given causal SNP estimated in the absence of LD with other such SNPs may correctly characterize the biological connections between the SNP and the trait. Therefore, for example, performing genetic analyses of African populations (that have lower levels of LD patterns for many SNP pairs than populations of European origin) has the potential to reduce bias in the estimated effects of functional SNPs on a trait caused by the presence of LD between functional loci. This condition is, however, not sufficient because of the possible presence of hidden gene/gene interaction effects, gene/environment correlations, and gene/environment interaction effects.
Human lifespan and many other aging, health and longevity related traits are multifactorial phenotypes, that is, they are affected by many genetic and non-genetic factors. The relationships between genes and these phenotypes have special features that distinguish them from other complex traits, influence methods of their genetic analyses, and affect the interpretation of the research results. The genetic variants that influence aging, health, and longevity related traits generate age dependent changes in the population genetic structure, i.e., changes in the frequencies of genetic variants and in the levels of linkage disequilibrium (LD) among them. This feature has important implications for studies focused on the replication of GWAS research findings: independent populations involved in such studies often have different genetic structures, due in part to the differences in the population age distribution at the time of biospecimen collection. As a result, the frequencies of the genetic variants associated with these traits and their LD patterns may differ even if the genetic structures in the corresponding population cohorts were the same at birth.
Detecting statistically significant associations of genetic variants with complex traits is not the end of the genetic analyses. One reason is that the relationship between a detected marker SNP and the complex trait of interest is not, necessarily, a causal one. More often these relationships serve as proxies for the real effect of some unobserved causal SNPs (due to linkage disequilibrium (LD) between the marker and causal SNPs), and, hence, do not have a direct biological effect on the phenotype. To generate insights about the biological mechanisms responsible for the trait’s variability one has to identify the causal SNPs responsible for the association signal. To identify such SNPs a number of efficient fine-mapping procedures have been recommended. The main limitation of existing methods is that they seek to identify a single causal variant which is independent of (not in LD with) other causal variants. Since this is not sufficiently realistic, a new approach that allows for efficient detection of multiple causal variants has been proposed. The case where two or more causal SNPs are in LD creates additional problems for interpretation of the results of genetic association studies.
In this paper we show that the estimates of the effects of a causal SNP on lifespan depend on the genetic structure of the population under study (e.g., the level of LD of the SNP with other causal SNPs). Genetic association studies of this trait using data from populations with different LD levels are likely to produce different results. We show that differences in population genetic structures can explain why genetic variants favorable for longevity in one population appear as harmful risk factors in another population. Population structure may also be responsible for the age-specific effects of genetic variants on mortality risk. Differences in genetic structures in distinct populations may be responsible for the low level of replicability of GWAS of human aging, health, and longevity related traits.
I stumbled upon an interesting open access paper a few days ago, linked below, in which the authors present their view of immunosenescence, the age-related failure of the immune system, as being in part a process wherein some cells of the adaptive immune system change their characteristics and function to become more like innate immune system cells. It makes for interesting reading, though it is worth bearing in mind that the immune system as a whole is fantastically complex, and in many ways still a dark and unmapped forest. It is easy to theorize unopposed when there is such a lot of empty space remaining on the map, making it hard to argue concretely about the relative importance of various mechanisms and observations. This poor understanding of the intricacies of the immune system is why autoimmune diseases and immune aging are largely lacking in effective treatments, and why the best of the prospective cures are those that sidestep the entire question of specific causes and mechanisms in face of the Gordian strategy of destroying the entire immune system in order to start over with new stem cells and immune cells.
As you might know, the immune system of most higher animals is two-layered. The layer that evolved first, and which remains the entirety of the immune system in lower animals such as insects, is known as the innate immune system. It reacts quickly, generates inflammation, and reacts in the same, predictable way to every threat. It has no memory and does not reconfigure its operations in response to circumstances and history. Later in evolutionary history, a second layer known as the adaptive immune system came into being, a more sophisticated set of functions resting on top of the existing innate mechanisms. The innate immune system reacts to intruders, and then the adaptive immune system records the nature of the threat and responds in its own manner, augmenting the attack. As the name suggests, the adaptive immune system maintains a memory and adjusts its operations in order to more aggressively destroy pathogens that it has encountered in the past. As anyone in the field will tell you, however, this high level picture of cleanly divided dualism is overly simplistic, however. There are numerous grey areas and incompletely understood complexities at the border between the two sides of the immune system.
Given that the adaptive immune system can adapt, its failure with aging is in large part a matter of acquired misconfiguration. There is only a small influx of new immune cells in adults, and this puts an effective limit on the number of immune cells that is supported at any one time. The inevitable problem in a space-limited system that keeps a continual record of history is that it runs out of space: evolutionary pressures produced the trade-off of a system that works very well out of the gate in young people, but fails sometime in later life. An old adaptive immune system is burdened with too many cells devoted to memory and too few cells devoted to attacking new threats. That is on top of the progressive failures that occur due to the the growing burden of the molecular damage that accompanies aging: persistent metabolic waste products such as cross-links and lipofuscin, mitochondrial damage, diminished stem cell activity, and so forth. The innate immune system has its own problems that arise from this damage, but is less prone of the issue of misconfiguration.
Understanding exactly how aging progressively harms the intricate choreography of the immune response is a massive project, and nowhere near completion. It is possible to judge how far along researchers are in this work by the side effect of the quality of therapies for autoimmune disease, which are malfunctions in immune configuration, and largely incurable at the present time. From a practical point of view, and as mentioned above, the best prospects for effective treatments in the near future involve destroying and recreating the immune system. That works around our comparative ignorance by removing all of the problems that researchers don’t understand in addition to ones that they do. Destroying the immune system can only be done with chemotherapy at the moment, which no-one would undergo unless there was no choice in the matter given that it has significant negative effects on long-term health, but once new methods of selective immune cell destruction are developed, lacking side-effects, then we can start to talk about treating immune aging by rebooting the immune system.
Convergence of Innate and Adaptive Immunity during Human Aging
Aging is associated with a general decline in immune function, contributing to a higher risk of infection, cancer, and autoimmune diseases in the elderly. Such faulty immune responses are the result of a profound remodeling of the immune system that occurs with age, generally termed as immunosenescence. While the number of nave T cells emerging from the thymus progressively decreases with age as a result of thymic involution, the memory T cell pool expands and exhibits significant changes in the phenotype and function of antigen-experienced T cells, particularly evident in the CD8+ T cell compartment. Chronic immune activation due to persistent viral infections, such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), is one of the main drivers contributing to the accumulation of highly differentiated antigen-specific CD8+ T lymphocytes that have characteristics of replicative senescence. In combination with the depletion of the peripheral pool of nave T cells, the accumulation of these terminally differentiated T cells with age skews the immune repertoire and has been implicated in the impaired immune responses to new antigens and vaccination in the elderly
Natural killer cells and CD8+ T lymphocytes are the two major cell lineages with constitutive cytotoxic activity and have a crucial role in the recognition and killing of abnormal cells. However, the paradigm for the recognition of target cells is fundamentally different between these two cell types: conventional CD8+ T cells rely on the T cell receptor (TCR) to recognize specific peptides presented by major histocompatibility complex class-I (MHC-I) molecules, whereas NK cells use a repertoire of germ line-encoded receptors to detect “missing self” or “altered-self” antigens and directly kill abnormal cells, without prior sensitization. Besides antigen specificity, the development of immunological memory is conventionally another distinctive feature between NK and T cells, categorizing them into distinct arms of the immune system and the innate and adaptive immune system, respectively.
Nevertheless, accumulating evidence supports the existence of NK cell memory, as well as evidence for TCR-independent responses mediated by CD8+ T lymphocytes, suggesting that the conventional limits between the innate and adaptive arms of the immune system may be not as distinct as first thought. NK and T lymphocytes have a common origin from a lymphoid progenitor cell in the bone marrow, and recent comparative proteomic and transcriptomic studies have demonstrated a remarkably close proximity between effector CD8+ T lymphocytes and NK cells, reiterating an evolutionary ancestry and shared biology between the two cell lineages.
An increasing body of literature reveals the existence of subsets of T cells with features that bridge innate and adaptive immunity. These cells typically co-express a TCR and NK cell lineage markers, distinguishing them from NK cells and other innate lymphoid cells, which lack the expression of a TCR or somatically rearranged receptors. Functionally, innate-like T cells respond to TCR ligation but are also able to respond rapidly to danger signals and pro-inflammatory cytokines, independently of TCR stimulation, resembling innate cells. Recently, subsets of conventional CD8+ T cells expressing NK cell markers and intraepithelial T cells have been included in this vaguely defined group of innate-like T cells. Despite the similarities in phenotype and function, there are clear differences in ontogeny and tissue distribution between them.
In this review, we will discuss recent evidence that aging is associated with the expansion of a subset of conventional CD8+ T cells with phenotypic, functional, and transcriptomic features that resemble NK cells. Such innate-like CD8+ T cells have the characteristics of terminally differentiated T cells, and the acquisition of functional NK receptors is most likely part of a general reprograming of the CD8+ T cell compartment during human aging, to ensure broad and rapid effector functions. We propose that innate-like CD8+ T cells share important features with other innate-like T cells; however, fundamental differences in origin and development separate them from truly innate cells. Interestingly, these cells are also differentially affected by aging, suggesting distinct roles in immune responses at different times of life. Evidence indicates that chronological aging is associated with accumulation of cells combining features of both the innate and adaptive arms of the immune system, most likely to compensate for functional defects of conventional NK and CD8+ T cells with age. We propose that senescent CD8+ T cells should not be seen as a dysfunctional population but instead a functionally distinct subset, which uses recently acquired NK cell machinery to maintain rapid effector functions throughout life. Contrary to the classic paradigm that peripheral TCR ligation is essential for T cell activation, this subset of highly differentiated T cells has impaired TCR responsiveness and may be non-specifically activated by inflammatory cytokines or after ligation of innate receptors. The switch to an innate mode of function may shed light on the mechanisms that allow highly differentiated CD8+ T cells to maintain functionality, despite the loss of TCR signal functions.
Our understanding of the physiological significance of the expression of NKRs on T cells is still incomplete, and the identification of the molecular mechanisms and the transcriptional regulators underpinning the development of innate features in T cells is essential. Most importantly, it will be important to understand how the intersection between innate and adaptive immune features may be manipulated to enhance immune function and to use this information to develop new approaches to improve immunity in the elderly.
There are many possible answers to the question of why women have a longer life expectancy than men, but no real consensus on which of the candidate mechanisms are the important ones. It is interesting to note that, in an age in which rejuvenation therapies are starting to arrive, the research community has a better idea of how to bring aging under medical control, and thus make natural variations in longevity irrelevant, than of how to definitively determine the mechanisms causing those natural variations between groups of humans. Fully understanding our biochemistry is a massive undertaking, far greater in scope than merely wrestling degenerative aging into submission by addressing its root causes. Biology is enormously complex, and working with statistical demographic data or evolutionary theory doesn’t tend to produce firm answers, only helping to narrow down the directions for further inquiry.
People worldwide are living longer, healthier lives. A new study of mortality patterns in humans, monkeys and apes suggests that the last few generations of humans have enjoyed the biggest life expectancy boost in primate history. The gains are partly due to advances in medicine and public health that have increased the odds of survival for human infants and reduced the death toll from childhood illness. Yet males still lag behind females – not just in humans but across the primate family tree, the researchers find. “The male disadvantage has deep evolutionary roots.”
An international team compiled records of births and deaths for more than a million people worldwide, from the 18th century to the present. The data included people in post-industrial societies such as Sweden and Japan, people born in pre-industrial times, and modern hunter-gatherers, who provide a baseline for how long people might have lived before supermarkets and modern medicine. The researchers combined these measurements with similar data for six species of wild primates that have been studied continuously for three to five decades, including sifaka lemurs, muriqui monkeys, capuchins, baboons, chimpanzees and gorillas. The data confirm a growing body of research suggesting that humans are making more rapid and dramatic gains than ever before seen in the primate family tree. For example, in the last 200 years life expectancy in Sweden has jumped from the mid-30s to over 80, meaning that a baby born today can hope to live more than twice as long as one born in the early 19th century. The data show that today’s longest-lived human populations have a similar 40- to 50-year advantage over people who live traditional lifestyles, such as the Hadza hunter-gatherers of Tanzania and the Ach people of Paraguay.
In contrast, these modern hunter-gatherers – the best lens we have into the lives of early humans – live on average just 10 to 20 years longer than wild primates such as muriquis or chimpanzees, from which human ancestors diverged millions of years ago. “We’ve made a bigger journey in lengthening our lifespan over the last few hundred years than we did over millions of years of evolutionary history.” One indicator of healthcare improvement is infant mortality, which strikes fewer than 3 in 1000 babies born in Sweden or Japan today. But it was more than 40 times higher for those born two centuries ago, and is still high among hunter-gatherers and wild primates.
The researchers also studied lifespan equality, a measure similar to income equality that indicates whether longevity is distributed evenly across society, or only enjoyed by a few. They found that, for both humans and wild primates, every gain in average lifespan is accompanied by a gain in lifespan equality. That is, for a population to be very long-lived, everyone must benefit more or less equally, with fewer individuals left behind. The researchers were surprised to find that the longevity of human males has yet to catch up with females, and the improvements in males aren’t spread as evenly. A girl born in Sweden in the early 1800s could expect to outlive her male counterparts by an average of three to four years. Two hundred years later, despite Swedes adding 45 years to their average lifespan, the gulf that separates the sexes has barely budged. The life expectancy gender gap isn’t just true for humans. Females outlived males in almost every wild primate population they looked at.
In the field of tissue engineering, this is the era of organoids. Researchers are limited in the size of tissue they can produce because of the lack of a robust method of generating the blood vessel networks needed to support large tissue sections, but are otherwise making significant progress in the generation of functional organ tissue. Initially this is producing the greatest benefit for further research and development, allowing tests to be conducted in living tissue at a much faster pace and lower cost. For many tissue types, however, organoids also offer the possibility of benefits realized through transplantation, as in many cases they are capable of integrating with existing organ tissue to improve its function.
Scientists report using human pluripotent stem cells to grow human intestinal tissues that have functioning nerves in a laboratory. The paper puts medical science a step closer to using human pluripotent stem cells (which can become any cell type in the body) for regenerative medicine and growing patient-specific human intestine for transplant. “One day this technology will allow us to grow a section of healthy intestine for transplant into a patient, but the ability to use it now to test and ask countless new questions will help human health to the greatest extent.” This ability starts with being able to model and study intestinal disorders in functioning, three-dimensional human organ tissue with genetically-specific patient cells. The technology will also allow researchers to test new therapeutics in functioning lab-engineered human intestine before clinical trials in patients.
Researchers started out by subjecting human pluripotent stem cells to a biochemical bath that triggers their formation into human intestinal tissue in a petri dish. The process was essentially the same as that used in a 2010 study, which reported the first-ever generation of three-dimensional human intestinal organoids in a laboratory. Intestinal tissues from the initial study lacked an enteric nervous system, which is critical to the movement of waste through the digestive tract and the absorption of nutrients. The gastrointestinal tract contains the second largest number of nerves in the human body. When these nerves fail to work properly it hinders the contraction of intestinal muscles. To engineer a nervous system for the intestinal organoids already growing in one petri dish, researchers generated embryonic-stage nerve cells called neural crest cells in a separate dish. The neural crest cells were manipulated to form precursor cells for enteric nerves. The challenge at this stage was identifying how and when to incorporate the neural crest cells into the developing intestine. “We tried a few different approaches largely based on the hypothesis that, if you put the right cells together at the right time in the petri dish, they’ll know what do to. It was a long shot, but it worked.” The appropriate mix caused enteric nerve precursor cells and intestines to grow together in a manner resembling developing fetal intestine.
A key test for the engineered intestines and nerves was transplanting them into a living organism – in this case laboratory mice with suppressed immune systems. This allowed researchers to see how well the tissues grow and function. Study data show the tissues work and are structured in a manner remarkably similar to natural human intestine. They grow robustly, process nutrients and demonstrate peristalsis – series of wave-like muscle contractions that in the body move food through the digestive tract.
The first rejuvenation therapies to work well enough to merit the name will be based on the SENS vision: that aging is at root caused by a few classes of accumulated cell and tissue damage, and biotechnologies that either repair that damage or render it irrelevant will as a result produce rejuvenation. Until very recently, no medical technology could achieve this goal, and few research groups were even aiming for that outcome. We are in the midst of a grand transition, however, in which the research and development community is finally turning its attention to the causes of aging, understanding that this is the only way to effectively treat and cure age-related disease. Age-related diseases are age-related precisely because they are caused by the same processes of damage that cause aging: the only distinctions between aging and disease are the names given to various collections of symptoms. All of frailty, disease, weakness, pain, and suffering in aging is the result of accumulated damage at the level of cells and protein machinery inside those cells. Once the medical community becomes firmly set on the goal of repairing that damage, we’ll be well on the way to controlling and managing aging as a chronic condition – preventing it from causing harm to the patient by periodically repairing and removing its causes before they rise to the level of producing symptoms and dysfunction. The therapies of the future will be very different from the therapies of the past.
The full rejuvenation toolkit of the next few decades will consist of a range of different treatments, each targeting a different type of molecular damage in cells and tissues. In this post, I’ll take a look at the likely order of arrival of some of these therapies, based on what is presently going on in research, funding, and for-profit development. This is an update to a similar post written four years ago, now become somewhat dated given recent advances in the field. Circumstances change, and considerable progress has been made in some lines of research and development.
1) Clearance of Senescent Cells
It didn’t take much of a crystal ball four years ago to put senescent cell clearance in first place, the most likely therapy to arrive first. All of the pieces of the puzzle were largely in place at that time: the demonstration of benefits in mice; potential means of clearance; interested research groups. Only comparatively minor details needed filling in. Four years later no crystal ball is required at all, given that Everon Biosciences, Oisin Biotechnologies, SIWA Therapeutics, and UNITY Biotechnology are all forging ahead with various different approaches to the selective destruction of senescent cells. No doubt many groups within established Big Pharma entities are also taking a stab at this, more quietly, and with less press attention. UNITY Biotechnology has raised more than $100 million to date, demonstrating that there is broad enthusiasm for this approach to the treatment of aging and age-related disease.
With the additional attention and funding for this field, more methods of selective cell destruction have been established, and there is now a greater and more detailed understanding of the ways in which senescent cells cause harm, contributing to the aging process. Senolytic drugs that induce apoptosis have been discovered; senescent cells are primed to enter the programmed cell death process of apoptosis, and so a small nudge to all cells via a drug treatment kills many senescent cells but very few normal cells. Researchers have established that senescent cells exist in the immune system, and may be important in immune aging. Similarly, the immune cells involved in the progression of atherosclerosis are also senescent, and removing them slows the progression of that condition. Other research has shown that removing senescent cells from the lungs restores lost tissue elasticity and improves lung function. Beyond these specific details, senescent cells clearly contribute to chronic inflammation in aging, and that drives the progression of near all common age-related conditions. The less inflammation the better. These effects are caused by the signals secreted by senescent cells: that their harm is based on signaling explains how a small number of these cells, perhaps 1% by number in an aged organ, can cause such widespread havoc.
2) Immune System Destruction and Restoration
At the present time it is a challenge to pick second place. A number of fields are all equally close to realization, and happenstance in funding decisions, regulatory matters, or technical details yet to be uncovered will make the difference. The destruction and recreation of the immune system wins out because it is already possible, already demonstrated to be successful, and just missing one component part that would enable it to be used by ordinary, healthy, older people. At present researchers and clinicians use chemotherapy to destroy immune cells and the stem cells that create them. Repopulation of the immune system is carried out via cell transplants that are by now a safe and proven application of stem cell medicine, little different from the many varieties of first generation stem cell therapy. This approach has been used to cure people with multiple sclerosis, and has been attempted with varying degrees of success for a number of other autoimmune conditions for going on fifteen years now: there are researchers with a lot of experience in this type of therapy.
The catch here is that chemotherapy is a damaging experience. The cost of undergoing it is high, both immediately, and in terms of negative impact on later health and life expectancy, similar to that resulting from a life spent smoking. It only makes sense for people who are otherwise on their way to an early death or disability, as is the case for multiple sclerosis patients. However, there are a number of approaches very close to practical realization that will make chemotherapy obsolete for the selective destruction of immune cells and stem cells – approaches with minimal or no side-effects. A combined approach targeting c-kit and CD47 was demonstrated earlier this year, for example. Sophisticated cell targeting systems such as the gene therapy approach developed for senescent cell clearance by Oisin Biotechnologies could also be turned to stem cell or immune cell destruction, given suitable markers of cell chemistry. There are quite a few of these, any one of which would be good enough.
Replacing the chemotherapy with a safe, side-effect-free treatment would mean that the established programs for immune system restoration could immediately expand to become a useful, effective treatment for immunosenescence, the age-related failure of the immune system. This is in part a problem of configuration: a lifetime of exposure to persistent pathogens such as herpesviruses leaves too much of the immune system uselessly devoted to specific targets that it cannot effectively clear from the body, and too little left ready to fight new threats and destroy malfunctioning cells. Then there are various forms of autoimmunity that become prevalent in older people, not all of which are in any way fully understood – consider just how recently type 4 diabetes was discovered, for example. Clearing out the entire immune system, all of its memory and quirks, and restarting it fresh with a new supply of stem cells is a good approach to many of the issues in the aged immune system. Not all of them, but many of them, and considering the broad influence immune function has over many other aspects of health and tissue function, it seems a worthwhile goal.
3) Clearance of the First Few Types of Amyloid
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Fight Aging! Reports from the front line in the fight …
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