Fight Aging! Newsletter, December 20th 2021

The Adult Changes in Thought (ACT) study is a long-standing, Seattle-based observational study of more than 5,000 participants older than 65. Based on the longitudinal data of over 3,000 ACT study participants, researchers have now found that subjects who underwent cataract surgery had nearly 30% lower risk of developing dementia from any cause compared with those who did not. This lowered risk persisted for at least a decade after surgery. Cataract surgery was also associated with lower risk of Alzheimer disease dementia specifically. The mechanisms by which cataract surgery and lessened dementia risk are associated was not determined in this study. Researchers hypothesize that people may be getting higher quality sensory input after cataract surgery, which might have a beneficial effect in reducing the risk of dementia.

Twenty percent of adults older than 65 years in the United States experience significant sensory impairment, such as vision or hearing loss, even with correction. Addressing sensory loss that affects a substantial portion of older adults may be a potentially modifiable risk factor for dementia in late life. Because sensory impairments and dementia are both strongly associated with aging, more knowledge about the association between sensory impairment and dementia may have important implications for individual and global public health, particularly if interventions to improve sensory function reduce dementia risk.

Visual impairment is an important dementia risk. Cataract is a leading cause of blindness worldwide, affecting more than 35 million people globally and causing blindness in approximately 20 million. Cataract affects most older adults at risk of dementia. However, there are conflicting results regarding the association between cataract extraction and cognitive impairment or dementia.

We hypothesized that older adults with cataract who undergo cataract extraction may have a lower risk of developing dementia compared with participants who do not undergo cataract surgery or participants who undergo other eye procedures that do not restore vision, such as glaucoma surgery. Previous studies exploring this association have been limited by small sample sizes, cross-sectional designs, and varying qualities of dementia assessment. More importantly, these studies have failed to account for healthy patient bias (i.e. when surgery is more likely in healthier individuals with the same cataract severity).

In total, 3038 participants were included, with mean age at first cataract diagnosis of 74.4 years. Based on 23,554 person-years of follow-up, cataract extraction was associated with significantly reduced risk (hazard ratio, 0.71) of dementia compared with participants without surgery after controlling for years of education, self-reported White race, and smoking history and stratifying by apolipoprotein E genotype, sex, and age group at cataract diagnosis. Similar results were obtained in marginal structural models after adjusting for an extensive list of potential confounders. Glaucoma surgery did not have a significant association with dementia risk. Similar results were found with the development of Alzheimer's disease dementia.

Life expectancy is constantly rising and median lifespan is increasing but maximum lifespan is not. Although the number of centenarians (100 years old or older) is doubling every ten years, maximum longevity remains the same. The longest living person died in 1997 at the age of 122 and this record has not been beaten. It was suggested that longevity records cannot be overcome unless a scientific breakthrough in delaying aging would happen. First, such scientific breakthroughs are happening now and drugs that slow down aging are becoming available. Yet, these drugs have not yet been employed in a sufficient number of humans for a sufficiently long period of time to make demographic impact. This breakthrough will eventually break the lifespan record. However, such a breakthrough is not even necessary. A mere application of standard medical care to centenarians, as rigorously as to younger adults, would probably extend lifespan beyond 122, even without the need of a scientific breakthrough.

We will discuss here that an increase of average lifespan without maximal lifespan is happening because advanced medical interventions are available for everyone except the oldest old, exactly those who may live longer than 122, if treated. While a thirty-year old patient with heart disease may become a candidate for heart transplantation, it would be ridiculous even to mention heart transplantation for a supercentenarian. In other words, life-extending care is not available (usually with best intentions; in many cases, patients themselves do not want aggressive medical interventions) exclusively and specifically to those who can beat the 122 lifespan record. Furthermore, since their death certificates state "old age" instead of a specific disease, most centenarians do not receive treatment but even a diagnosis. As we will discuss, this explains why the 122 year record is not broken despite the absence of any biological constraints.

The lifespan of slowly aging centenarians can be extended by providing them adequate medical care. But can an average person beat the 122-year-old record? Currently, medical interventions extend lifespan mostly by extending morbidity span. By now several interventions were shown to increase healthspan and lifespan in animals. Hypothetically, these interventions may transform an average person into a slowly aging centenarian.

Rapamycin and everolimus are available to delay age-related diseases and increase health span in pets and humans. Rapamycin-based therapy may include medications such as metformin, aspirin, angiotensin-2 antagonists, PDE5 inhibitors, DHEA, melatonin and several others as well as fasting or low carb diets. In theory, anti-aging therapy may make an average human resemble centenarians, aging slower and developing diseases later. Due to anti-aging treatment, these centenarians will reach 100 in good health, just as genetic centenarians. These centenarians should seek thorough medical care, according to their lower biological age, not according to their chronological age. This, however, will require the revolution of policies, ethical standards and legal issues to ensure maximum longevity.

Investigators put either functional or locked running wheels into the cages of 3-month-old lab mice, which are metabolically equivalent to 25-year-old humans. A month of steady running was enough to substantially increase the quantity of neurons and other cells in the brains of marathoner mice when compared with those of sedentary mice. Next, the researchers collected blood from marathoner and, as controls, sedentary mice. Then, every three days, they injected other sedentary mice with plasma (the cell-free fraction of blood) from either marathoner or couch-potato mice. Each injection equaled 7% to 8% of the recipient mouse's total blood volume. (An equivalent amount in humans would be about 1/2 to 3/4 of a pint).

On two different lab tests of memory, sedentary mice injected with marathoner plasma outperformed their equally sedentary peers who received couch-potato plasma. In addition, sedentary mice receiving plasma from marathoner mice had more cells that give rise to new neurons in the hippocampus (a brain structure associated with memory and navigation) than those given couch-potato plasma transfusions.

Turning to an examination of proteins in the marathoner mice's blood, the team identified 235 distinct proteins, of which 23 were scarcer and 26 more abundant in marathoner compared with couch-potato mice. Several of these differentially expressed proteins were associated with the complement cascade - a set of about 30 blood-borne proteins that interact with one another to kick-start the immune response to pathogens. Removing a single protein, clusterin, from marathoner mice's plasma largely negated its anti-inflammatory effect on sedentary mice's brains. No other protein the scientists similarly tested had the same effect. Clusterin, an inhibitor of the complement cascade, was significantly more abundant in the marathoners' blood than in the couch potatoes' blood.

Further experiments showed that clusterin binds to receptors that abound on brain endothelial cells, the cells that line the blood vessels of the brain. These cells are inflamed in the majority of Alzheimer's patients, and research has shown that blood endothelial cells are capable of transducing chemical signals from circulating blood, including inflammatory signals, into the brain. Clusterin by itself, even though administered outside the brain, was able to reduce brain inflammation in two different strains of lab mice in which either acute bodywide inflammation or Alzheimer's-related chronic neuroinflammation had been induced.

Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration. The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampu, yet little is known about the factors and mechanisms that mediate these effects. Here we show that 'runner plasma', collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation.

Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer's disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise.

Research conducted 2018 found that senescent cells accumulated in mouse models of Alzheimer's disease where they contributed to brain cell loss, inflammation, and memory impairment. When the researchers used a therapy to clear the senescent cells, they halted disease progression and cell death. "However, until now, we didn't know to what extent senescent cells accumulated in the human brain, and what they actually looked like. It was somewhat like looking for the proverbial needle in a haystack except we weren't sure what the needle looked like."

Using sophisticated statistical analyses, the research team was able to evaluate large amounts of data. In total, they profiled tens of thousands of cells from the postmortem brains of people who had died with Alzheimer's disease. The researchers' plan was to first determine if senescent cells were there, then how many there were and what types of cells they were. They succeeded. The team found that approximately 2% of the brain cells were senescent and that the senescent cells were neurons, which are the fundamental units in the brain that process information and are the workhorses of memory. They also are the primary cells that are lost in Alzheimer's disease.

Next, the team sought to determine if the senescent neurons had tangles - abnormal accumulations of a protein called tau that can collect inside neurons in Alzheimer's disease. These tangles closely correlate with disease severity, meaning that the more tangles individuals have in their brains, the worse their memory. The researchers found that the senescent neurons not only had tangles but that they overlapped to the point that it was hard to distinguish between them.

Senescent cells contribute to pathology and dysfunction in animal models. Their sparse distribution and heterogenous phenotype have presented challenges to their detection in human tissues. We developed a senescence eigengene approach to identify these rare cells within large, diverse populations of postmortem human brain cells. Eigengenes are useful when no single gene reliably captures a phenotype, like senescence. They also help to reduce noise, which is important in large transcriptomic datasets where subtle signals from low-expressing genes can be lost. Each of our eigengenes detected ∼2% senescent cells from a population of ∼140,000 single nuclei derived from 76 postmortem human brains with various levels of Alzheimer's disease (AD) pathology.

More than 97% of the senescent cells were excitatory neurons and overlapped with neurons containing neurofibrillary tangle (NFT) tau pathology. Cyclin-dependent kinase inhibitor 2D (CDKN2D/p19) was predicted as the most significant contributor to the primary senescence eigengene. RNAscope and immunofluorescence confirmed its elevated expression in AD brain tissue. The p19-expressing neuron population had 1.8-fold larger nuclei and significantly more cells with lipofuscin than p19-negative neurons. These hallmark senescence phenotypes were further elevated in the presence of NFTs. Collectively, CDKN2D/p19-expressing neurons with NFTs represent a unique cellular population in human AD with a senescence-like phenotype.

Elimination of senescent cells (senolysis) was recently reported to improve normal and pathological changes associated with aging in mice. However, most senolytic agents inhibit antiapoptotic pathways, raising the possibility of off-target effects in normal tissues. Identification of alternative senolytic approaches is therefore warranted. Here we identify glycoprotein nonmetastatic melanoma protein B (GPNMB) as a molecular target for senolytic therapy. Analysis of transcriptome data from senescent vascular endothelial cells revealed that GPNMB was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). GPNMB expression was upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.

Genetic ablation of Gpnmb-positive cells attenuated senescence in adipose tissue and improved systemic metabolic abnormalities in mice fed a high-fat diet, and reduced atherosclerotic burden in apolipoprotein E knockout mice on a high-fat diet. We then immunized mice against Gpnmb and found a reduction in Gpnmb-positive cells. Senolytic vaccination also improved normal and pathological phenotypes associated with aging, and extended the male lifespan of progeroid mice. Our results suggest that vaccination targeting seno-antigens could be a potential strategy for new senolytic therapies.

NewLimit will start by deeply interrogating epigenetic drivers of aging and developing products that can regenerate tissues to treat specific patient populations. We will start by using primary human cells and reference species to develop machine learning models on what chromatid features change with age, which of these changes may be causal to the aging process, and finally develop therapies that could slow, halt, or reverse this process.

You can take a skin cell from an old mouse and clonally turn it into a newborn mouse with an entire life ahead of it. Remarkably, to accomplish this magic, you only treat the cells with four types of proteins. In a system as complex as mammalian biology, with billions of DNA base pairs and tens of thousands of proteins, all it takes is dosing four proteins for a couple weeks to completely change what the cell "is". NewLimit plans to initially focus on this mechanism: epigenetic reprogramming. Put simply, we want to figure out a way to restore the regenerative potential we all had when we were younger, but somehow lost.

We've raised 105 million initially from the founders to help get the company off the ground, with additional funding available upon reasonable progress. We expect capital will not be the limiting factor for the next few years. We may raise external funding as well down the road.

The new study builds on decades of research showing that when old mice are given blood from young mice, youthful features are restored to many cells and tissues. But until now, it was unclear which components of young blood confer these rejuvenating effects. Researchers collected serum, the fraction of blood that remains after removing blood cells and clotting factors, from young mice and injected it into aged mice with injured muscle. Mice that received young serum showed enhanced muscle regeneration and functional recovery compared to those that received a placebo treatment, but the serum's restorative properties were lost when extracellular vesicles (EVs) were removed, indicating that these vesicles mediate the beneficial effects of young blood.

Delving deeper, the researchers found that EVs deliver genetic instructions, or mRNA, encoding the anti-aging protein Klotho to muscle progenitor cells, a type of stem cell that is important for regeneration of skeletal muscle. EVs collected from old mice carried fewer copies of the instructions for Klotho than those from young mice, prompting muscle progenitor cells to produce less of this protein. With increasing age, muscle doesn't heal as well after damage because scar tissue is deposited instead of restoring original muscle structure. In earlier work, the team showed that Klotho is an important regulator of regenerative capacity in muscle progenitor cells and that this protein declines with age.

The new study shows for the first time that age-related shifts in EV cargo contribute to depleted Klotho in aged stem cells, suggesting that EVs could be developed into novel therapies for healing damaged muscle tissue.

In vascular diseases like atherosclerosis, arterial walls thicken and harden, disturbing blood flow. That leads to a buildup of plaque, which could ultimately lead to blocked arteries. Studies have linked microRNA-92a (miR-92a) to dysfunction of the endothelial cells that line the inside of blood vessels, which means miR-92a is considered a biomarker of the disease.

While a miR-92a inhibitor treatment exists (and has been tested in animals and humans), it cannot yet be delivered directly to the blood vessel site, and therefore is not as effective as it could be. Several years ago, researchers developed a nanoparticle - a polyelectrolyte complex micelle - to deliver the inhibitor directly to inflamed blood vessel cells. This nanoparticle uses a peptide to target the vascular cell adhesion molecule 1 (VCAM-1), which is found in high levels in inflamed endothelial cells but remains low in healthy cells. Once the peptide finds the molecule, it delivers the miR-92a inhibitor directly to the damaged cells.

The team has tested the nanomedicine in a mouse model and found that it reduces the size of vascular lesions. They also found that the treatment inhibited stenosis, the remodeling of vascular tissue that causes it to close off.

Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction.

In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted, or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate, or prevent age-related pathologies.

Angiotensin II can cause oxidative stress and increased blood pressure that result in long term cardiovascular pathologies. Here we evaluated the contribution of cellular senescence to the effect of chronic exposure to low dose angiotensin II in a model that mimics long term tissue damage. We utilized the INK-ATTAC (p16Ink4a-Apoptosis Through Targeted Activation of Caspase 8) transgenic mouse model that allows for conditional elimination of p16Ink4a-dependent senescent cells by administration of AP20187.

Angiotensin II treatment for 3 weeks induced ATTAC transgene expression in kidneys but not in lung, spleen, and brain tissues. In the kidneys increased expression of ATM, p15, and p21 matched with angiotensin II induction of senescence-associated secretory phenotype genes MMP3, FGF2, IGFBP2, and tPA. Senescent cells in the kidneys were identified as endothelial cells by detection of GFP expressed from the ATTAC transgene and increased expression of angiopoietin 2 and von Willebrand Factor, indicative of endothelial cell damage. Furthermore, angiotensin II induced expression of the inflammation-related glycoprotein versican and immune cell recruitment to the kidneys.

AP20187-mediated elimination of p16-dependent senescent cells prevented physiologic, cellular, and molecular responses to angiotensin II and provides mechanistic evidence of cellular senescence as a driver of angiotensin II effects. In conclusion, the low dose, prolonged angiotensin II exposure is associated with the induction of senescence in kidneys and the promotion of an inflammatory microenvironment through both secreted factors and immune cells. Endothelial cells appear to be a major cell type impacted. The elimination of senescent cells in the INK-ATTAC transgenic model prevents these effects of angiotensin II and reveals a novel pathophysiologic mechanism amenable to targeting by senolytic drugs in development.

Skeletal muscle displays remarkable plasticity upon exercise and is also one of the organs most affected by aging. Despite robust evidence that aging is associated with loss of fast-twitch (type II) muscle fibers, the underlying mechanisms remain to be elucidated. Here, we identified an exercise-induced long noncoding RNA, CYTOR, whose exercise responsiveness was conserved in human and rodents. Cytor overexpression in mouse myogenic progenitor cells enhanced myogenic differentiation by promoting fast-twitch cell fate, whereas Cytor knockdown deteriorated expression of mature type II myotubes. Skeletal muscle Cytor expression was reduced upon mouse aging, and Cytor expression in young mice was required to maintain proper muscle morphology and function.

In aged mice, rescuing endogenous Cytor expression using adeno-associated virus serotype 9 delivery of CRISPR activation reversed the age-related decrease in type II fibers and improved muscle mass and function. In humans, CYTOR expression correlated with type II isoform expression and was decreased in aged myoblasts. Increased CYTOR expression, mediated by a causal cis-expression quantitative trait locus located within a CYTOR skeletal muscle enhancer element, was associated with improved 6-minute walk performance in aged individuals from the Helsinki Birth Cohort Study. Direct CYTOR overexpression using CRISPRa in aged human donor myoblasts enhanced expression of type II myosin isoforms.

In conclusion, the long noncoding RNA Cytor was found to be a regulator of fast-twitch myogenesis in aging. These findings may lead to the future development of interventions to improve myogenesis.

A decline in mitochondrial function has long been associated with age-related health decline. Several lines of evidence suggest that interventions that stimulate mitochondrial autophagy (mitophagy) can slow aging and prolong healthy lifespan. Prohibitins (PHB1 and PHB2) assemble at the mitochondrial inner membrane and are critical for mitochondrial homeostasis. In addition, prohibitins (PHBs) have diverse roles in cell and organismal biology.

Mitophagy is the breakdown of damaged mitochondria via autophagy. Mitophagy and mitochondrial dynamics (fission/fusion) are linked in maintaining mitochondrial quality control. Excessive mitochondrial fusion or impaired mitochondrial fission is an underlying factor in the age-related decline in mitophagy, which is associated with senescence and aging. PHB2 binds to microtubule-associated protein 1A/1B-light chain 3 (LC3) to promote degradation of the mitochondria by an autophagosome. A second study found further support that PHBs can promote mitophagy. This study found a new axis for mitophagy by PHB2: loss of PHB2 prevented mitophagy by destabilizing PINK1, which inhibited recruitment of Parkin, optineurin, and ubiquitin. Conversely, increasing PHB2 levels was found to increase mitophagy by promoting Parkin recruitment.

In conclusion, PHBs have therapeutic potential in a variety of age-related diseases. Targeting PHBs may represent an attractive therapeutic target to counteract aging and age-onset disease.

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors, and metalloproteinases, with autocrine and paracrine activities.

Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in which context angptl2 was identified as a SASP factor, describe the experimental evidence showing that angptl2 is a marker of senescence in vitro and in vivo, and discuss the impact of angptl2-related senescence in both physiological and pathological conditions. Future work is needed to demonstrate whether the senescence marker angptl2 is a potential clinical biomarker of age-related diseases.

We know that the world's population is currently living longer. This is especially problematic, given the increase in the prevalence of chronic conditions resulting from an increased aging population, thus negatively affecting the healthspan and quality of life of the affected individuals. This review discussed the effects of aging on the cardiovascular system and established an increased predisposition of cardiovascular pathologies in the geriatric population due to molecular, structural, and functional changes in both the cardiac and vascular systems. Longevity molecular pathways exist to maintain the homeostasis of the cardiovascular system and promote health. Autophagy is at the interlink of these pathways.

Although autophagy is downregulated as people age, stimulation of this pathway through caloric restriction, intermittent fasting, and supplementation of pharmacologic agents can reinstate autophagy in older individuals. Induced autophagy promotes the longevity of cardiovascular health, thereby instigating the role of autophagy in the prevention of chronic conditions such as cardiovascular ailments. Strong evidence for this notion has emerged from studies using genetically modified mice defective in genes, transcription factors, and proteins essential for autophagy and as such failed to show improvements in cardiovascular health when caloric restriction, intermittent fasting, and pharmacologic agents are implemented.

To summarize, future research should be directed toward human studies or human tissues in vitro. This will allow for a clearer understanding of the role of autophagy on the longevity pathways and cardiovascular disease prevention in humans. In addition, future research should evaluate how the beneficial effects of autophagy can be implemented reproducibly and on large scales in the population.

The incidence of cognitive decline increases with age, especially for impairments in episodic memory and spatial memory, which are typically associated with the hippocampus. Deterioration in the morphometry of the hippocampus, as well as the integrity of its circuitry, are thought to be critical in the progression of these deficits. There is increasing evidence that some forms of physical exercise protect against spatial memory decline; however, the results have been inconsistent in both humans and animals. Although several explanations have been proposed, the precise mechanisms by which exercise improves brain health remain unclear. We recently demonstrated that an optimal period of exercise in aged mice is required to activate neurogenesis in a growth hormone-dependent manner, resulting in the restoration of hippocampal-dependent spatial learning. What remains elusive, however, is how the structure and functional circuitry of the hippocampus is remodeled and what drives these connectivity changes following exercise in the aged brain.

In studies showing that adult hippocampal neurogenesis (AHN) leads to cognitive changes during aging, little has been reported about how exercise affects the structure and functional circuitry responsible for behavioral changes, and whether any circuitry changes are dependent on the level of neurogenesis. Magnetic resonance imaging (MRI) studies in humans have revealed that older adults show significant increases in hippocampal volume and functional connectivity after aerobic exercise intervention. Similarly, rodent MRI studies have demonstrated that running increases hippocampal volume and blood flow. However, the specific circuitry related to improved cognition and whether this is directly regulated by neurogenesis remain unknown.

To address these issues, we applied structural, diffusion, and functional MRI (fMRI) longitudinally following different periods of exercise in mouse models. We hypothesized that behavioral performance in aged mice depends on dentate gyrus (DG) connectivity driven by exercise-induced neurogenesis. To determine the contribution of AHN to this process, we specifically ablated doublecortin (DCX)-positive newborn neurons using our novel knockin DCXDTR mouse line. Our results reveal that improved spatial learning in aged mice after exercise is due to enhanced DG connectivity, particularly the strengthening of the DG-Cornu Ammonis 3 (CA3) and the DG-medial entorhinal cortex (MEC) connections in the dorsal hippocampus. Moreover, we provide evidence that this change in circuitry is dependent on the activation of neurogenesis.