Fight Aging! Newsletter, July 26th 2021

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How long older individuals prefer to live given hypothetical adverse changes in health and living conditions has been insufficiently studied. The current study addressed how long individuals want to live and under a set of adverse hypothetical life scenarios. The sample was a population of adults aged 60 years and above in Norway from the NORSE study. The results suggest a relatively high preferred life expectancy (PLE) compared to findings from other investigations, although comparisons across culture and context are inherently problematic.

The desire to live is considered a basic driving force, but high life expectancy may also be related to individual unfinished business aims, and tasks one would like to finish before dying. Older age translated into higher PLE, particularly among the very old respondents. In our study, there was a tendency for longer PLE among men compared to women, but the difference was not significant. Thus, we did not replicate findings from other studies reporting that women prefer somewhat shorter lives.

Adverse health and living conditions prevalent at older ages may reduce preference to live longer. This study investigated the relationship between six hypothetic situations and PLE: dementia, spousal death, becoming a burden, poverty, loneliness, or chronic pain. The finding that dementia had the strongest negative effect on PLE concurs with prior studies suggesting a widespread fear of dementia. Chronic pain was also strongly associated with lower PLE in this study. For many people, chronic pain has been found to reduce quality of life and limit opportunities for social activities. It is also noteworthy that the third-highest ranked reason for lower PLE in this study was the belief that one represents a burden. Perceiving oneself to be a burden can relate to other outcomes in terms of self-view, including a loss of dignity at older ages.

Slightly above half of the respondents stated that poverty would decrease how long they would like to live. Poverty increases the risk of lower quality of life, autonomy, and wellbeing at older ages and relates to a greater disease burden. Severe poverty is rare in Norway. Older age groups have experienced rapid decreases in poverty levels over the last decades. Nevertheless, the fear of poverty in old age can still be widespread among older individuals, many of whom have grown up in a context where poverty was more prevalent.

In this session, Steve Horvath, professor at the University of California Los Angeles, provided an overview of the current state of the epigenetic clock field and the new developments in it. Then he went on to talk about what is missing in regards to methylation clocks and the longevity field itself, as well as what might be the next steps - the holy grails we should strive to get to. He also went to address some of the common misconceptions tied to epigenetic clocks at the end.

In this session, Morgan Levine, Assistant Professor at Yale, gave a sneak peek into the new epigenetic clock they are developing that is able to probe into multiple organ systems, as well as on a new approach how to calculate clocks that is much more reliable, enabling to generate insights from methylation clocks with much smaller samples required. The second talk was given by Jamie Justice, Assistant Professor at Wake Forest, that covered the current ways and strides the longevity field is making towards validating biomarkers of aging through clinical trials, shown on examples of a few senolytic trials they made. In the end she also explained how exactly the TAME trial, which she is a coordinator of, should serve as a vehicle for the field to move further and have a flagship trial to validate new aging biomarkers against in the future.

In this session, Gordan Lauc (Genos Glyco and GlycanAge) and Vadim Gladyshev (Harvard), gave their point of view on biomarkers and aging clocks development. Gordan Lauc went through the interesting glycomic data they recently and insights it generated about aging and menopause, exceptional predictive capability of glycans for hypertension, and much more. Vadim Gladyshev then went through the approach to molecular signatures and biomarkers that they are employing to find and test interventions to extend lifespan. Part of it is also a new epigenetic clock called scAge functioning on a single cell basis. This clock enabled them to find when aging actually begins during embryonic development.

Fibrosis and wound healing are essentially interwoven processes, driven by a cascade of injury, inflammation, fibroblast proliferation and migration, matrix deposition and remodelling. Pathological fibrogenesis that occurs in many diverse organs and diseases is a dynamic process involving complex interactions between epithelial cells, fibroblasts, immune cells (macrophages, T-cells), and/or endothelial injuries.

As a response to lung injury, many interrelated wound-healing pathways are activated in order to facilitate the repair, turnover, and adaptation of lung tissue. However, although their aetiology and causative mechanisms varies, the different fibrotic lung diseases all fail to properly eliminate inciting factors, leading to continued tissue damaging with an abnormal and exaggerated accumulation of extracellular matrix (ECM) components and collagen deposition. Another hallmark of lung fibrosis is that older individuals display impaired ability to restore tissue homeostasis, heal wounds and resolve fibrosis, resulting in tissue scarring and irreversible organ damage

The number of senescent cells gradually increases with age, and the presence of senescent cells is a common finding in age-related pathologies. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. Our understanding of the biology of senescence in an evolutionary context has led us to think about cellular senescence as an essential mechanism of antagonistic pleiotropy. This concept encompasses processes that are meant to be beneficial to the health of young organisms (as a strong tumour-suppressor mechanism, or integrating physiologically programmed mechanisms during development), but also can demonstrate deleterious effects in older organisms, most likely by promoting chronic inflammation and fibrosis that leads to both degenerative and hyper-plastic pathologies.

Antagonistic pleiotropy is key to understanding many aspects of lung fibrosis, especially the relationship between aging, cellular senescence, and lung fibrosis. In the lung, there is a relatively straightforward relationship to several environmental factors, such as tobacco smoke, air pollutants, environmental antigens, or infections, so the setting in which cellular senescence develops is fraught with dangerous stressors, including DNA damage and telomere attrition, oncogenic signalling activation, epigenomic stress, redox imbalance, or mitochondrial biogenesis dysfunction. This attribute might also explain the vulnerability of the lung to increases in senescence-inducing conditions that promote the loss of architectural integrity and elasticity, and subsequent pulmonary function impairment.

Whilst work continues to explore the possible therapeutic benefits of senolysis, we recently suggested that it is important to ask what evolutionary forces might have been behind the emergence of cellular senescence. Entry into the senescent state appears to be regulated, presenting questions about why such a response should have evolved. It seems a priori unlikely that a purely negative action would be favoured by natural selection. In terms of potential benefits, cellular senescence is often regarded as an anti-cancer mechanism, since it limits the division potential of cells. However, many studies have shown that senescent cells often also have carcinogenic properties. Furthermore, other studies have shown that cellular senescence is beneficially involved in wound healing, development, and tissue repair.

We recently brought these findings and ideas together and concluded that evolutionary logic strongly supports the idea that the latter positive contributions are the main reason for the evolution of cellular senescence. We further suggested that, since the immune system appears to play a role in clearing senescent cells once they have performed their temporary functions, the observed age-related accumulations of senescent cells might arise simply because the immune system had to strike a balance between false negatives (overlooking some senescent cells) and false positives (destroying healthy body cells).

The importance of understanding the role of senescent cells is further indicated by recent senolysis studies in mice, where it was found that treatment with senolytics resulted in a substantial increase in mean and median survival times. However, in each of the studies there was much less increase in the maximum survival time. Such an outcome is only possible if, following senolytic treatments, the deaths that are postponed to produce the increased mean / median lifespans become concentrated in the interval prior to the relatively unaltered maximum lifespan. Such a phenomenon constitutes a 'compression of mortality', which needs to be explained

We developed computer simulations of three possible mechanistic scenarios in order to gain a better understanding of possible modes of action of senolytic treatments. Scenario A, which supposes simply that senescent cells are all-important in ageing, was shown to be incompatible with experimental findings. Scenario B, which allows for other forms of damage to be involved and which also allows for senescent cells to drive these other forms of damage to some degree, was also found not to explain the data, although it does generate some interesting behaviours. In contrast, Scenario C proved to have the potential to explain the experimental findings. Scenario C includes the idea that the immune system plays an important role in removing senescent cells and related damage, but that this 'repair capacity' of the immune system is also negatively affected by senolytic drugs. In the case of a single senolytic treatment the repair capacity can recover, but if the treatment is given continuously (as in all the experimental studies), the repair capacity is chronically reduced. This leads to an accelerated accumulation of damage, causing a faster increase of mortality.

Physical function (i.e., aerobic capacity, gait speed, and muscle strength) has been proposed as a biomarker of healthy ageing, as it is predictive of adverse health events, disability, and mortality. The role of physical exercise as a therapeutic strategy for prevention of both disease and the associated decline in functional capacity has been emphasised repeatedly. Supervised exercise interventions in hospitalised older people (aged ≥75 years) have been proved to be safe and effective in preventing or attenuating functional and cognitive decline.

Unfortunately, few studies have explored the potential role of tailored physical activity guidelines to maximise exercise-related effect on function. Also, exercise has not been fully integrated into primary or geriatric medical practice and is almost absent from the core training of most medical doctors and other health-care providers. Physical trainers should be included in health-care systems to help manage physical exercise programmes for older patients.

Taking into consideration current evidence about the benefits of exercise for frail older adults, it is unethical not to prescribe physical exercise for such individuals. To promote healthy and dignified ageing, it is therefore essential to help health-care systems to more efficiently implement evidence-based exercise programmes for frail older adults in all community and care settings.

Commensal microbes provide a critical contribution to aging. Caenorhabditis elegans grown without a bacterial microbiome (axenic) live twice as long as those grown conventionally. Similarly, most analyses have suggested that Drosophila lifespan is extended by axenic growth, though that relationship depends on both growth conditions and the details of how such studies are performed. For example, lack of a microbiome, particularly early in life, may limit the development of a robust innate immune response and alter the expression of stress-response genes, and therefore sensitize an individual to later microbial challenge. Moreover, the presence of a microbiome can compensate for a diet with low protein content, perhaps because the bacteria themselves act as a food source. Multiple mechanisms, therefore, contribute to the modulation of lifespan in axenic conditions.

Additionally, some studies link the microbiome-dependence of lifespan to specific commensal species, or to the interaction of specific commensals with variants in the host genome or compounds in the environment. For example, in C. elegans, at least some of the linkage between the microbiome and aging seems to be mediated by specific microbially-secreted metabolites. Such specificity, however, is difficult to understand in light of the generality of the phenomenon, given the variety of species and experimental paradigms in which it has been observed.

Here, we perform genome-wide gene expression profiling of Drosophila raised either under conventional growth conditions or under axenic conditions. We find that approximately 70% of the systematic changes in gene expression that we observe with age under conventional conditions fail to happen when we grow the flies axenically. In essence, many of the typical correlates of Drosophila aging become uncoupled from the passage of time for the greater part of adulthood if the flies lack a bacterial microbiome.

Among the genes that do not show expected, time-dependent changes in expression when flies are raised axenically are those associated with two features of aging that are observed widely across animal evolution, a decline in the expression of stress-resistance genes and progressive activation of innate immunity, as well as others. Thus, while these processes are clearly critical regulators of organismal lifespan, our data suggest that they are separable from other aspects of the typical progression of age-associated changes in organismal gene expression. They seem, rather, to reflect a succession of strategies that the organism has evolved for different stages of its lifecycle in order to exist in a microbe-rich environment.

In contrast, genes associated with some age-correlated processes, including rhythmic behavior, maintenance of cuticular structure, olfaction, and a subset of metabolic and redox processes, show changes in level over time in the axenic state that are similar to those observed under conventional conditions, allowing us to use them as biomarkers to quantify the age-correlated physiological state of the germ-free animal. The experiments reported here, therefore, support the view that the organism is subject to a progression of separable processes that individually modulate organismal longevity, while also identifying biomarkers of a time-dependent, internal state of the animal that reflects its effective age.

Researchers have created an inflammatory clock of aging (iAge) which measures inflammatory load and predicts multi-morbidity, frailty, immune health, cardiovascular aging and is also associated with exceptional longevity in centenarians. The study identified the soluble chemokine CXCL9 as the strongest contributor to iAge. It is a small immune protein that is usually called into action to attract lymphocytes to the site of an infection. "But in this case we showed that CXCL9 upregulates multiple genes implicated in inflammation and is involved in cellular senescence, vascular aging, and adverse cardiac remodeling. Silencing CXCL9 reversed loss of function in aging endothelial cells in both humans and mice."

Results from the initial analysis, which also included information from comprehensive clinical health assessments of 902 individuals, were validated in an independent cohort of centenarians and all-cause mortality in the Framingham Heart Study. According to the researchers, when it comes to health and longevity, the "age" of one's immune system most certainly trumps the chronological information that can be derived from a driver's license. "On average, centenarians have an immune age that is 40 years younger than what is considered 'normal' and we have one outlier, a super-healthy 105 year-old man who has the immune system of a 25 year old."

Study results involving cardiac health were also validated in a separate group of 97 extremely healthy adults (age 25 - 90 years of age). Researchers found a correlation between CXCL9 and results from pulse wave velocity testing, a measure of vascular stiffness. "These people are all healthy according to all available lab tests and clinical assessments, but by using iAge we were able to predict who is likely to suffer from left ventricular hypertrophy (an enlargement and thickening of the walls of the heart's main pumping chamber) and vascular dysfunction."

The prospects of generating specialized cells in a dish that can be transplanted into patients to treat various diseases are encouraging. However, the immune system would immediately recognize cells that were recovered from another individual and would reject the cells. Hence, some scientists believe that custom cell therapeutics need to be generated from scratch using a blood sample from every individual patient as starting material. Researchers here followed a different approach, using gene editing to create 'universal stem cells' (named HIP cells) that are not recognized by the immune system and can be used to make "universal cell therapeutics."

The team tested the ability of these cells to treat three major diseases affecting different organ systems: peripheral artery disease; chronic obstructive pulmonary disease from alpha1-antitrypsin deficiency; and heart failure, increasingly a global epidemic with more than 5.7 million patients in the United States alone and some 870,000 new cases annually. The scientists transplanted specialized, immune-engineered HIP cells into mice with each of these conditions and were able to show that the cell therapeutics could alleviate peripheral artery disease in hindlimbs, prevent the development of lung disease in mice with alpha1-antitrypsin deficiency, and alleviate heart failure in mice after myocardial infarction.

One of the great benefits of this approach is that the strategy of immune engineering comes with a reasonable price tag. It would make the manufacturing of universal, high-quality cell therapeutics more cost effective, could allow future treatment of larger patient populations, and facilitate access for patients from underserved communities. "In order for a therapeutic to have a broad impact, it needs to be affordable. That's why we focus so much on immune-engineering and the development of universal cells. Once the costs come down, the access for all patients in need increases."

Scientists have explored using stem cell therapy as a way to regrow tissue after a heart attack. But introducing stem cells directly to the heart can be risky because they could trigger an immune response or grow uncontrollably, resulting in a tumor. Therefore, researchers have tried injecting exosomes - membrane-bound sacs containing proteins, lipids, and nucleic acids secreted by stem cells - into the heart, but they often break down before they can have therapeutic effects. Others have developed cardiac patches, or scaffolds that help implanted exosomes last longer, but they usually must be placed on the heart during open-chest surgery. Researchers wanted to develop an exosome solution that could be sprayed onto the heart through a tiny incision, avoiding major surgery.

The researchers mixed exosomes from mesenchymal stem cells with fibrinogen, a protein involved in blood clotting. They added this solution to a tiny, double-barreled syringe that contained a separate solution of another clotting protein called thrombin. When the team sprayed the solutions out of the syringe onto a rat's heart through a small chest incision, the liquids mixed and formed an exosome-containing gel that stuck to the heart. A mini-endoscope, inserted through a second small incision, guided the spray needle. In rats that had recently had a heart attack, the exosome spray lasted longer, healed injuries better and boosted the expression of beneficial proteins more than heart-injected exosomes. In pigs, the spray caused less severe immune reactions and surgical stress than open-chest surgery. The spray is a promising strategy to deliver therapeutic exosomes for heart repair.

Obesity, nonalcoholic fatty liver disease (NAFLD), and insulin resistance (IR) associated with visceral, hepatic, or ectopic fat are major risk factors for a number of chronic diseases including diabetes mellitus (DM), cardiovascular diseases, and cancer. These metabolic disorders are intrinsically involved in an energy imbalance between energy expenditure and calorie intake. An appropriate degree of calorie restriction (CR) ameliorates these disorders, and moreover, it is the only proven way to extend lifespan in mammals like rodents. It has already been shown in both primates and rodents that CR improves health, decreases age-related mortality, and extends lifespan.

The mitochondrial uncoupler 2,4-dinitrophenol (DNP) was widely used as a weight-loss agent in the 1930s; however, its use was accompanied by many severe adverse effects including hyperthermia, cataracts, agranulocytosis, and even death. These effects were ascribed to the narrow therapeutic window, and finally the FDA banned its use in 1938. Since then, the use of chemical mitochondrial uncouplers has been confined to their use as reagents for basic research. Nevertheless, there has been a revival in interest in their therapeutic applications, and attempts to discover safe chemical uncouplers have been made due to their energy-consuming benefit. In particular, liver-targeted mitochondrial uncoupling is a promising means of an efficacious and safe treatment for DM and hepatic steatosis.

Our initial screened compound cyanotriazole derivative 1 has a unique chemical structure different from any known mitochondrial uncouplers. We attempted to optimize it as a safe therapeutic option for metabolic disorders such as DM. In this optimization, we regarded safety as the most important factor; therefore, we primarily assessed organ distribution and the acute toxicity of the compounds as well as antidiabetic efficacy. We describe here the optimization process from initial screening hit compound to a liver-localized mitochondrial uncoupler OPC-163493, which recently demonstrated its potent antidiabetic and cardiovascular beneficial effects with acceptable safety.

Vascular aging is an independent risk factor for morbidity and mortality of age-related diseases, particularly cardiovascular diseases (CVDs) such as hypertension and atherosclerosis. Vascular aging is characterized by vascular stiffening, intimal and medial thickening, increased luminal diameter, reorganization of the extracellular matrix, and endothelial dysfunction. The theories for the mechanisms of vascular aging include inflammation, mitochondrial dysfunction, oxidative stress, telomere attrition, epigenetics, and autophagy.

Inflammaging occurs during physiological aging in the absence of an overt infection, which describes the low-grade, chronic systemic inflammation. Inflammaging plays a role in all age-related diseases such as CVDs, which affect the mortality and morbidity of elderly people. The activation of immune cells such as macrophages / monocytes and the endothelial cell dysfunction participates in vascular low-grade inflammatory processes.

Growing research has identified that hypoxia-inducible factor-1α (HIF-1α) has an important effect on the aging-related process, particularly regulating cardiovascular aging. Vascular endothelial growth factor (VEGF), which is regulated by HIF-1, is a significant regulator for angiogenesis and a vital player of vascular aging. The activity of HIF-1 decreases during aging and then downregulates the expression of VEGF and results in the impairment of angiogenesis. The research found that HIF-1α is involved in regulating vascular inflammation in macrophages by limiting excessive vascular remodeling. In conclusion, HIF-1α may be a potential therapeutic target in vascular diseases, particularly in vascular aging.

In recent years, through the growing investigations and the more in-depth understanding of aortic stiffness, it was found that aortic stiffness is not only related to increased risk of cardiovascular diseases and related mortality but also involved in the aging changes of brain and cognitive function. With advancing age, the aortic vessel wall's elastic fibers are gradually reduced and replaced by collagen fibers or deposition of calcification, which impairs aorta's elasticity and causes aortic stiffness. The stiffening and loss of recoil in the aorta would transmit excessive and damaging pulsatile load to the peripheral arteries of body organs. Theoretically, the brain is more susceptible to pulsatile damage due to its low-resistance and high-flow characteristics. Aortic stiffness was reported to be closely associated with cerebral structural changes, primarily the cerebral small vessel disease and brain atrophy. There have been studies that focus on the relationship between aortic stiffness and cognitive function. However, their results were inconsistent.

Among various pulse wave velocity (PWV) measurements for aortic stiffness, carotid-femoral PWV (cfPWV) that measure the PWV along the aortic and aortoiliac pathways is the recommended gold-standard non-invasive technique to assess aortic stiffness because of its reliability and feasibility, which is highly related with magnetic resonance imaging (MRI) directly measuring PWV. While brachial-ankle PWV (baPWV) or femorotibial PWV (ftPWV), the commonly used PWV index measured outside the main aortic track, reflects mainly the stiffness of the small arteries rather than pure aortic stiffness, its predicted value in cardiovascular disease is still controversial. Thus, considering the validation in clinic practice, we performed a systematic review and meta-analysis about the association between aortic stiffness measured using the validated aortic PWV and cognitive function, risk of cognitive impairment, or dementia to help clarify the association between aortic stiffness and cognitive function in the aging process.

Thirty-nine studies were included in the qualitative analysis, and 29 studies were included in the quantitative analysis. The aortic PWV was inversely associated with memory and processing speed in the cross-sectional analysis. In the longitudinal analysis, the high category of aortic PWV associated with a 44% increased risk of cognitive impairment compared with low PWV, and the risk of cognitive impairment increased 3.9% per 1 m/s increase in aortic PWV. Further, meta-regression analysis showed that age significantly increased the association between high aortic PWV and cognitive impairment risk.

The widespread improvement in global life expectancy at birth was one of the greatest achievements of the 20th Century. Today, most children born in high-income countries will live into their ninth decade, and possibly beyond. This represents a new reality for humanity. In 1816, for example, French children had a 1 in 4 chance of making it to 70 years; today life expectancy in France is higher than 4 in 5.

The fact that a child born today is more likely to live to old age makes ageing well a new health priority. In fact, it's a multi-trillion value target. Imagine a health intervention that improved health and lowered mortality at every age such that overall life expectancy increased by one year. We calculate that such an intervention would be worth a staggering 37 trillion in present value terms in the United States (US). That's the total value of healthier ageing to the US population - both current and future - at an annual rate of 725 billion. Our research also shows that whilst longer lives are valuable, the most valuable health priority of all is to ensure that healthspan rises to match lifespan; and that the period many spend in poor health towards the end of life is made as small as possible.

Because ageing is a cumulative phenomenon, ageing well is a lifelong process. This process can be supported by critical shifts in public health, better individual life and career choices, and healthier living conditions. It will also require the development of new treatments that aren't just aimed at specific age-related diseases but which target ageing itself. This isn't reflected in current funding practices. The US spends more than 4 trillion on healthcare annually but only 2.6 billion is allocated to the National Institute of Aging, which mostly focuses on dementia. Given the scientific progress being made in the field of ageing, and the scale of the future health challenge, more resources need to be invested.

The need for more funding is based on recent scientific developments. Scientists understand the biological mechanisms of ageing now more than ever and agree on the factors that contribute to it. Drugs that target these factors are already being developed in laboratories and biotech companies around the world. Research and treatments aimed at single diseases, such as cancer and dementia, are important. But a broader focus on delaying or even reversing ageing has considerable advantages. Firstly, given the number of age-related diseases, any successful treatment to reverse or delay ageing will aggregate benefits across multiple disease fronts. And secondly, treatments that delay ageing are highly beneficial because they lessen the probability of disease. Most children born in high-income countries today will grow to be old. As a global community, we must ensure that our response to an ageing population goes beyond supporting the elderly to ensuring that the current young become the healthiest ever future old.

All cancers fall into just two categories, according to new research, based on the presence or absence of a protein called the Yes-associated protein, or YAP. YAP is either on or off, and each classification exhibits different drug sensitivities or resistance. YAP plays an important role in the formation of malignant tumours because it is an important regulator and effector of the Hippo signaling pathway. "Not only is YAP either off or on, but it has opposite pro- or anti-cancer effects in either context. Thus, YAPon cancers need YAP to grow and survive. In contrast, YAPoff cancers stop growing when we switch on YAP."

Many YAPoff cancers are highly lethal. In their new research, scientists show that some cancers like prostate and lung can jump from a YAPon state to a YAPoff state to resist therapeutics. When cancer cells are grown in a dish in a lab setting, they either float or stick down. The team of researchers found that YAP is the master regulator of a cell's buoyancy, where all the floating cells are YAPoff, and all the sticky cells are YAPon. Changes in adhesive behavior are well known to be associated with drug resistance, so their findings implicates YAP at the hub of this switch.

"The simple binary rule we uncovered may expose strategies to treat many cancer types that fall into either the YAPoff or YAPon superclasses. Moreover, since cancers jump states to evade therapy, having ways to treat either the YAPoff and YAPon state could become a general approach to stop this cancer from switching types to resist drug treatments."