One noteworthy difference between the biochemistry of young and old individuals is a greater presence of oxidative molecules, resulting from dysfunctional cells, inflammatory processes, and other issues. As a consequence, there are also many more oxidized molecules, changed from their original structure and now either broken or actively harmful. Cells clear out this sort of oxidative damage constantly, and are quite efficient at this sort of maintenance until levels of oxidization become high, but they nonetheless struggle with some particularly toxic or resilient oxidized molecules, even in smaller amounts. A good example of the type is 7-ketocholesterol, a form of oxidized cholesterol. It is primarily understood as an important contributing cause of atherosclerosis via its detrimental effects on the macrophages responsible for clearing lipids from blood vessel walls, but there is evidence for it to contribute to other age-related conditions as well.
Cholesterols exist both inside and outside of the cell, as they are important components of all cellular membranes, but these and other nonpolar substances are transported in the plasma via lipoprotein particles. Low density lipoprotein (LDL) is the principle carrier of cholesterol to peripheral tissue. All of the components of LDL are susceptible to oxidation to produce an oxidized form of LDL (OxLDL). OxLDL has been linked to a variety of pathologies. Oxidation of the cholesterol in LDL produces several oxidation products including 7-ketocholesterol (7KC), which is the most abundant oxysterol present in OxLDL. We believe that it is important to distinguish between the effects of OxLDL and that of unsequestered 7KC, as many studies fail to account for this important difference in how 7KC interacts with the cell.
OxLDL is not the only source of 7KC within the body. 7KC can be produced endogenously by a series of oxidation or, much less commonly, enzymatic reactions. It can also be ingested directly in food, however the liver is well equipped to process and rid the body of exogenous toxins, so 7KC is not acutely poisonous to ingest. However, endogenously produced, unsequestered 7KC can wreak havoc inside of most cells. Unesterified 7KC can be found within membranes of organelles where it disrupts fluidity and signaling pathways, causing cellular damage via multiple stress-response pathways. These stress-response pathways induce a vicious cycle by increasing the population of reactive oxygen species, which in turn increases the oxidation of cholesterol and production of 7KC. Particularly in people with already-compromised cholesterol pathways, 7KC buildup can be overwhelming and cause significant damage to membranes, pathways, and overall cell function.
7KC is the most abundant oxysterol in both oxLDL particles and atherosclerotic plaques, indicating the significant role 7KC plays in the progression of atherosclerosis. 7KC has been shown to induce macrophage reprogramming, foam cell formation, and oxiapoptophagy in a multitude of cell types. In atherosclerotic plaques, this results in the deposition of calcium-laden apoptotic bodies, leading to subsequent calcification of the blood vessel.
It has been shown that oxysterols are likely a cause of altered brain cholesterol metabolism which is an integral part of Alzheimer’s disease, Parkinson’s disease, and other aspects of neurological aging. It is not yet fully understood whether 7KC can cross the blood-brain barrier, but 7KC is highly toxic to neuronal cells and should certainly form spontaneously inside of them with age. Additionally, 7KC is implicated in macular degeneration as it is a major component of the drusen within the retina. 7KC can also damage the liver by disrupting membrane rafts and fenestrations. Lastly, 7KC is also characterized in congenital disorders such as sickle cell, Niemann Pick, and other lysosomal storage disorders. Ambiguous links between many of these diseases, particularly atherosclerosis and neurodegeneration, further implicates 7KC as an unexplored target in many diseases.
We propose that 7KC could be an effective therapeutic target due to its implication in a wide variety of diseases. Although the abundance of 7KC has not yet been strongly correlated to aging or the severity of different pathologies, there is clear evidence to show its destructiveness in biological systems. As more studies are conducted on toxic oxysterols in aging and disease, we hope that more will become known about 7KC abundance in different cells and tissues. This would increase the potential of 7KC as a therapeutic target for various diseases, especially those specifically associated with aging. Considering nonenzymatic oxysterol accumulation, particularly 7KC, as an integral factor in disease progression could change the way we identify and treat these diseases, offering new and possibly broadly effective therapeutics.
The adaptive immune system of an older person is a very different beast in comparison to that of the younger self. It has lost the supply of new T cells due to atrophy of the thymus, and the remaining population of T cells becomes ever more damaged, misconfigured, strange, and different. The immune system as a whole is complex enough to still be hiding many unexplored details, even in this era of biotechnology. Here, researchers outline a novel discovery in the immune function of supercentenarians. It seems that at very advanced ages, some T cells start to undertake radical shifts in function in order to compensate somewhat for the growing lack of capacity. It remains to be seen whether or not this only occurs to a significant degree in a minority of the population, and is thus a feature of supercentenarians because it increases the odds of survival.
Supercentenarians, people who have reached 110 years of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed single-cell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from 7 supercentenarians and 5 younger controls. We identified a marked increase of cytotoxicCD4 T cells as a signature of supercentenarians. This characteristic is very unique to supercentenarians, because generally CD4 T cells have helper, but not cytotoxic, functions under physiological conditions. Furthermore, single-cell T cell receptor sequencing of two supercentenarians revealed that cytotoxic CD4 T cells had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15-35% of the entire CD4 T cell population.
The cytotoxic CD4 T cells exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of cytotoxic CD8 T cells. This indicates that cytotoxic CD4 T cells utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Indeed, cytotoxic CD4 T cells extracted from supercentenarians produced IFN-γ and TNF-α upon ex vivo stimulation. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.
Dogs are an interesting species when it comes to the study of aging. Firstly they are much closer to human metabolism and cellular biochemistry than mice, and secondly selective breeding has generated lineages with a very wide range of sizes and life spans. Thirdly, they occupy a good compromise position in the range of life spans, study cost, and similarity to humans. Mice live short lives, so studies are rapid and comparatively cheap, but there are sizable, important differences between mouse and human biochemistry. Humans live so long that most studies of aging are simply out of the question. Even in non-human primates that live half or less as long as we do, a study of aging and calorie restriction has lasted for decades, and few organizations can or will commit to that sort of effort.
Interest has picked up in recent years in the dog as a model of aging, to be used in the development of therapies to slow or reverse progression of aging. This is illustrated by the activities of the Dog Aging Project, for example, which seeks to obtain data on mTOR inhibitor therapies via their use in companion animals. Given this increased interest, researchers have started to catalog the holes in present knowledge. Even though dogs are very well studied, there is plenty to room to improve the understanding of how the mechanisms of aging progress and are influenced by genetics in this species.
Several genes have been shown to affect the body size variability of dogs, which is unmatched by any other mammalian species. Importantly, dogs also show marked differences in their expected lifespan in connection with body mass. On average, giant sized breeds (above 50 kg) have an expected lifespan of 6-8 years, while small sized breeds (below 10 kg) can live up to 14-16 years. This wide range of expected lifespans, together with other aspects, has made dogs promising as model organisms for aging research. Despite the huge progress in understanding the genetic basis of morphological variability of dogs, still very little is known about the functional relevance of canine homologs of conserved longevity genes. Currently, this may stand as an obstacle in the way of effectively utilizing dogs as aging models. As dogs can provide unique insights into many aspects of human aging, the current lack of detailed information about the canine genetic pathways of aging should be overcome by future research approaches. In this review, we provide an overview of the evolutionary conserved biological mechanisms that contribute to aging, following the Hallmarks of Aging classification, and we summarize current knowledge about these pathways in dogs.
The DNA repair machinery involves divergent pathways, each aimed to correct certain forms of DNA damage. These protective mechanisms have been in the focus of cancer and aging research for a long time. Polymorphisms in several genes of the DNA damage response machinery have been linked to longevity in humans. Intriguingly, no canine progeria syndrome, resulting from DNA repair deficiency, has been documented in the scientific literature. On the other hand, several studies that investigated various forms of canine cancer revealed alterations in the DNA repair machinery, which corresponded to findings in human cancers. While these findings clearly promote the dog as a natural model of human cancers, it is still unclear how exactly variations in DNA repair capacity contribute to the expected lifespan of dogs.
Telomere shortening is a characteristic only of somatic cells, while in germ line cells, telomere sequences are constantly restored by telomeraseenzymes. The limited proliferative potential of somatic cells may seem disadvantageous for an individual, yet it may increase fitness by limiting the growth of malignant cells. Contrary to mice, dogs were reported to have low or no telomerase expression in normal somatic tissues, a pattern similar to that in humans. Tumors in dogs often showed high levels of telomerase expression, similarly to human malignancies. Although very little is known about the molecular mechanisms regulating telomere maintenance and cell cycle arrest in dogs, such findings indicate that dogs may also share basic telomere biology with humans. Importantly, telomere length was shown to be variable across different dog breeds and was in correlation with expected lifespan. Also, telomere length in individual dogs was found to decrease with age, similarly as described in humans.
Although age associated changes in chromatin structure and DNA methylation patterns have been reported in several model animals, there can be major differences between species. For example, epigenetic regulation in C. elegans seems to be limited to chromatin remodeling by histone modifications, limiting its utilization as a model to study epigenetic changes in aging. In dogs, an increasing body of evidence has suggested epigenetic regulation is behind species and breed-specific traits. Importantly, a recent study demonstrated that changes in methylation status in DNA regions, which were homologous to regions with known age-sensitive methylation patterns in humans, were in strong correlation with chronological age in dogs and wolves. This finding supported the applicability of the dog as a model of age-related epigenetic changes, while it also provided a molecular approach to determine the biological age of individual canines.
Disruption of Proteostasis
Chaperone proteins play an important role in the post-translational maturation of nascent proteins by facilitating their folding. They also function as protectors of mature proteins under various stressful conditions, by helping to maintain their natural conformation and by preventing aggregation. In dogs, the few studies that investigated chaperone proteins in relation to aging reported similar age-related changes as in humans. For example, blood levels of the Hsp70 chaperone were shown to decrease with age in dogs, similarly to what had been previously reported in humans.
Deregulation of Nutrient Sensing
Cellular metabolism, protein synthesis, and autophagy are strictly regulated by various signaling pathways. Most of these have evolved to synchronize cell growth and metabolism with nutrient availability; hence, they are often referred to as nutrient sensing pathways. Many of them converge on the target of rapamycin (TOR) kinase. Importantly, the function of mTOR can be efficiently inhibited by rapamycin, which is an already approved immunosuppressant in human medicine, and therefore has been proposed as a promising anti-aging compound to be used in humans. However, it was reported to cause severe side effects in medical dosages. Therefore, optimal dosages, which do not cause undesirable syndromes, yet still exert longevity promoting effects should be carefully determined in preclinical studies. Actually, pharmaceutical studies have already been initiated to investigate the effects of rapamycin on the lifespan of dogs.
Nutrient sensing pathways converge on the regulation of mitochondrial activity, as these organelles are the main sources of energy (in the form of adenosine triphosphate, ATP) in eukaryotic cells under normal circumstances, when enough oxygen is present. The availability of nutrients determines the rate of mitochondrial respiration, which, however, generates not only ATP but also chemical by-products, including reactive oxygen species. The oxidative burden created by mitochondria may be especially high in neurons, which solely depend on aerobic mitochondrial respiration as energy source. The role of mitochondrial dysfunction and increased oxidative burden in neural aging has been investigated in dogs. In general, dog brains were shown to accumulate oxidative damage with age. Several mitochondrial diseases are known in dogs, which have human homologs, such as the sensory ataxic neuropathy found in Golden Retriever dogs or the familial dilated cardiomyopathy in Doberman Pinschers. As several promising anti-aging drugs are likely to be tested in dogs in preclinical studies, looking into their effects on mitochondrial function and testing their possible interactions with mitochondrial genotypes can be highly relevant for humans.
A marked elevation of senescent cell numbers was reported in old mice, although not in all tissues. Importantly, this accumulation process can result from both the increased generation of senescent cells and a decreased activity of macrophages that are able to eliminate aged or apoptotic cells from tissues. Little is known about the accumulation of senescent cells in canine tissues, although this phenomenon is also likely to show fundamental similarities with other mammalian species. As there is a growing interest toward pharmacological approaches to deplete senescent cells in tissues by specific apoptosis inducing agents (senolytic drugs), dogs may eventually be involved in testing these types of anti-aging interventions.
Stem Cell Exhaustion
Tissue renewal depends on the abundance and replicative capacity of tissue-specific stem cells. Hematopoietic stem cells (HSCs) were reported to have reduced replicative capacity in both aged mice and humans, mainly because of accumulating DNA damage. This reduction can explain the old age anemia of elderly people. Importantly, similar forms of age-associated changes in blood parameters, including anemia, were reported in dogs. Besides pharmacological interventions, stem cell therapy has also been suggested as a possible anti-aging intervention, with highlighted promises to treat certain forms of neurodegeneration. In this regard, stem cell therapy trials conducted on dogs affected by forms of neurodegeneration could represent a crucial step before progressing to human trials. In the case of the Golden Retriever model for Duchenne muscular dystrophy, successful stem cell-based interventions had actually preceded human clinical trials
Altered Intercellular Communication
In addition to hormones and metabolites, extracellular vesicles released by cells into the blood, called exosomes and ectosomes, have emerged as important transducers of various cellular signals. Consequently, exosomes may also modulate aging and neurodegeneration. Exosome research in dogs have been limited until recently. However, blood miRNA levels – which were hypothesized to be mainly found in exosomes – were reported to correlate with disease phenotypes in canine Duchenne muscular dystrophy. Similarly, miRNA content in circulating exosomes was shown to correlate with progression of secondary heart failure in cases of myxomatous mitral valve disease in dogs. Altogether, investigations about the connections between exosome content and aging or age-related pathologies in dogs may lead to the identification of diagnostic markers with potential translational prospects into human studies.
Alzheimer’s disease, vascular dementia, Lewy Body dementia. These diseases invoke dread in the bravest of us. The prospect of the loss of the memories of all that we hold dear and all that makes us who we are as individuals can be worse than the fear of death. A significant part of that fear is the knowledge that these diseases are considered, at this time, incurable.
But what if dementia is actually a reversible condition?
“We have come to fear Alzheimer’s disease as omnipotent. As impervious to any and all treatments,” writes Dale E. Bredesen, MD. “Until now. Let me say as clearly as I can. Alzheimer’s disease can be prevented, and in many cases its associated cognitive decline can be reversed.”1
Dr. Bredesen has developed a program he calls ReCODE which addresses 36 factors that contribute to Alzheimer’s disease.
For those who are unfamiliar with Dr. Bredesen, he has held faculty positions at UCLA, UCSD and UCSF—where he was a National Institute of Health postdoctoral fellow at the laboratory of Nobel Laureate Stanley B. Prusiner, MD, who was credited for the discovery of prions, the infectious agent in “mad cow disease.” Dr. Bredesen is currently affiliated with the Buck Institute, the only research institute singularly focused on the biology of aging, which he founded in 1998.
In a preliminary study that evaluated the effectiveness of Dr. Bredesen’s treatment regimen, nine of ten patients with memory loss due to subjective cognitive impairment, amnestic mild cognitive impairment or Alzheimer’s disease experienced improvement starting after 3-6 months.2 Six patients who had to quit working due to their condition were able to resume employment with better performance following treatment. The improvements observed in the study were sustained at follow-up.
“Results from the 10 patients reported here suggest that memory loss in patients with subjective cognitive impairment, mild cognitive impairment, and at least the early phase of Alzheimer’s disease, may be reversed, and improvement sustained, with the therapeutic program described here,” Dr. Bredesen wrote. “This is the first such demonstration.”
Following this study, Dr. Bredesen and colleagues documented 100 case studies of men and women treated with ReCODE.3 Follow-up revealed improvement, on average, in various test scores of cognitive function that would have otherwise declined. In some cases, improvement in imaging or electrophysiology was observed.
Bredesen’s Dementia Treatment Guidelines
In addition to restorative sleep, healthy activity levels, stress management and other positive lifestyle changes, Dr. Bredesen recommends regular monitoring of a number of blood factors and a supplement regimen that includes the B complex, vitamin C, vitamin D, vitamin E, vitamin K2, resveratrol, nicotinamide riboside, CDP-choline, acetyl-L-carnitine, coenzyme Q10 (CoQ10), PQQ and omega-3 fatty acids, and the herbs ashwagandha, Bacopa monnieri, gotu Kola, Lion’s mane and skullcap. He also recommends the herb rhodiola for those experiencing anxiety and/or stress and Tinospora cordifolia and guggul for people whose cognitive decline is associated with exposure to toxins such as mold. A trial to evaluate ReCODE that has enrolled 30 participants is in progress.
Lucidity in Dementia
A hint that dementia may be reversible can be inferred from patients who exhibit moments of lucidity, which often occurs near the end of their lives. It has often been observed by relatives or caregivers of dementia patients that these men and women will remember many things that had appeared to have been long forgotten, while speaking and acting normally.
Dementia Moments of Clarity
These moments or hours of clarity indicate that, when it comes to the brain, “all is not lost.” Although other factors in dementia patients’ day-to-day cognition are involved, this could help explain a phenomenon that can be attested to by every caregiver of “good days” experienced by those under their care.
“Paradoxical lucidity, if systematically confirmed, challenges current assumptions and highlights the possibility of network-level return of cognitive function in cases of severe dementias, which can provide insight into both underlying neurobiology and future therapeutic possibilities,” writes George A. Mashour and colleagues in Alzheimer’s & Dementia®, The Journal of the Alzheimer’s Association. “Our hypothesis is that the current framework of dementia as an inexorable and irreversible process of structural neuropathology must be revised to include a reversible and functional aspect of pathophysiology, even at late stages.”4
In an accompanying editorial titled, “Lucidity in dementia: A perspective from the NIA,” Basil A. Eldadah and his National Institute on Aging colleagues narrate the history of Ignaz Semmelweis, who proposed what was at that time the revolutionary idea that handwashing could help prevent the transmission of disease.5 Rather than being lauded as a hero, Semmelweis’ hypothesis was rejected by the prevailing medical establishment. Semmelweis spent the end of his life in a psychiatric hospital where he (ironically) died of an infection.
“The story of Semmelweis is one of numerous examples from the chapters of medical history that illustrate how dominant paradigms unwittingly create barriers that hinder innovation,” Dr. Eldadah and his associates write. “While prevailing theories tend to do best at explaining averages, they can break down at the extremes. And if a theory cannot adequately explain the extremes, then either the extremes are an artifact or the theory needs a second look.”
They note that the term “paradoxical” distinguishes the phenomenon of lucidity from the day to day variations in cognitive function that are observed in dementia’s earlier stages, and reflects our current rudimentary understanding. As an example, they describe the observation of early astronomers of planetary motion which was once explained by a complex system of orbits. This early hypothesis was eventually replaced by the heliocentric model which simply and logically explained the phenomenon.
The National Institute of Aging recently announced funding opportunities for research concerning lucidity in dementia.
Is Dementia Remission Possible?
“We’ve assumed that advanced dementia is an irreversible neurodegenerative process with irreversible functional limitations,” stated Dr. Mashour, who is a professor in the Department of Anesthesiology and Director of the Center for Consciousness Science at the University of Michigan. “But if the brain is able to access some sort of functional network configuration during paradoxical lucidity, even in severe dementia, this suggests a reversible component of the disease.”
While things seem hopeless to those afflicted by dementia now, the medical news is full of promising leads. Genetic modification, the potential development of drugs whose targets in one or more dementias are being revealed on an almost daily basis, discoveries concerning the relationship of dementias with pathogens and resultant inflammation, consideration of dementia as a whole-body disorder and more make this an exciting time in the field of geriatric neurology.
Believing that something is possible is a major step toward achieving a goal. With increased research efforts, medical science will have a greater understanding of dementia and we may begin to witness individuals who live to tell us how they beat it.
About the author:Dayna Dye has been a member of the staff of Life Extension® since shortly after its inception. She has served as the department head of Life Extension® Wellness Specialists, is the author of thousands of articles published during the past two decades in Life Extension® Update, Life Extension Magazine® and on www.lifeextension.com , and has been interviewed on radio and TV and in newsprint. She is currently a member of Life Extension’s Education Department.
Bredesen DE. The End of Alzheimer’s. New York: Avery. 2017. Print.
Bredesen DE. Aging (Albany NY). 2014 Sep;6(9):707-17.
Bredesen DE et al. J Alzheimers Dis Parkinsonism. 2018 Oct 19;8:450.
Mashour GA et al. Alzheimers Dement. 2019 Aug;15(8):1107-1114.
Eldadah BA et al. Alzheimers Dement. 2019 Aug;15(8):1104-1106.
Like most neurodegenerative conditions, Parkinson’s disease is driven in large part by the pathological aggregation of misfolded proteins, in this case α-synuclein. These solid deposits of protein spread from cell to cell, and are accompanied by a surrounding halo of harmful biochemical interactions. There is evidence for the protein aggregation of Parkinson’s disease to start in the gut and then spread to the brain. You might look at a recent paper that discusses whether or not we should consider Parkinson’s to be two diseases with a similar outcome, one in which the α-synuclein aggregation originates in the gut, and the other in which it originates in the brain. In the research noted here, scientists are following the gut origin hypothesis and targeting α-synuclein there in order to slow or reverse the progression of Parkinson’s disease.
Aggregates of the protein alpha-synuclein arising in the gut may play a key role in the development of Parkinson’s disease (PD). Investigators are testing the hypothesis that by targeting the enteric nervous system with a compound that can inhibit the intracellular aggregation of alpha-synuclein, they can restore enteric functioning in the short term, and possibly slow the progressive deterioration of the central nervous system in the long term. “The concept is that aggregates of the protein alpha-synuclein, thought to play a key role in the disease, arise within the enteric nervous system (ENS) and travel up the peripheral nerves to the central nervous system (CNS) where they ultimately cause inflammation and destruction of parts of the brain. Targeting the formation of alpha-synuclein aggregates in the ENS may therefore slow the progression of the disease.”
Alpha-synuclein is one of the defensive proteins produced by enteric nerves when they encounter infections. In children with acute bacterial gastrointestinal (GI) infections, for example, intestinal nerves produce alpha-synuclein. In children who have undergone intestinal transplants and who are prone to GI infections, investigators have shown that enteric neurons start making alpha-synuclein at the time of acute viral infections, and this outlasts the infection by many months, protecting nerve cells for prolonged periods of time. Within a nerve cell, alpha-synuclein could envelop invading viruses and disrupt their replication. It could also attach itself to small vesicles containing neurotransmitters and be released from the nerve cell hitching a ride with them. Once on the outside, it can attract protective immune cells from surrounding tissues.
To determine whether targeting alpha-synuclein within enteric neurons might help patients with PD, researchers are currently conducting clinical trials with a compound called ENT-01, a synthetic derivative of squalamine, a compound originally isolated from dogfish bile. It displaces alpha-synuclein from nerve cell membranes and restores the normal electrical activity of enteric neurons. Investigators completed a 50-patient Phase 2a study (RASMET) in patients with PD in 2018, which corrected constipation, a common symptom of PD, in more than 80% of participants, with the dose titrated up for each patient until a response was obtained. “The RASMET study demonstrated that the ENS is not irreversibly damaged in patients with PD. We believe that this is the first demonstration of the reversal of a neurodegenerative process in humans.” Possible benefits were also observed in motor and non-motor symptoms such as hallucinations, depression, and cognitive function. A 110-patient double-blind, placebo-controlledPhase 2b trial (KARMET) evaluating the effect of oral ENT-01 tablets on constipation and neurologic symptoms is currently being conducted.
Magnetic resonance imaging (MRI) is an imaging study that allows your physician to see detailed pictures of your organs and tissues. The MRI machine uses a large magnet, radio waves and a computer to take detailed cross-sectional pictures of your internal organs and tissues.1
The scanner looks like a tube with a table that enables you to slide into the tunnel of the machine to gather data. Unlike CT scans or X-rays that use ionizing radiation known to damage DNA, the MRI uses magnetic fields.
Images from an MRI give physicians better information about abnormalities, tumors, cysts and specific organ problems with your heart, liver, uterus, kidneys and other organs.
In some instances, your physician may want an enhanced MRI, one using a contrast agent or dye to improve the clarity of the images produced. According to a recent international poll,2 a majority of radiologists avoid informing patients when deposits of toxic contrast agents are discovered.
FDA Guidance on Gadolinium
Gadolinium is the contrast agent of choice in about one-third of cases.3 It’s injected into your body, allowing for greater detail to show up in the MRI images. There’s a price for this, however, as gadolinium is a highly toxic heavy metal.
To reduce its toxicity, the gadolinium is administered with a chelating agent.4 However, research suggests as much as 25% of the gadolinium injected in certain patients is not excreted,5,6 and deposits are still found in some patients long afterward.
In 2015, the U.S. Food and Drug Administration (FDA) began investigating the potential health effects from brain deposits of gadolinium, and released guidelines7 on the use of gadolinium-based contrast agents (GBCAs) to lower any potential risk.
Two years later, the agency issued an update8 saying “Gadolinium retention has not been directly linked to adverse health effects in patients with normal kidney function,” and that the benefits of GBCAs outweigh potential risks. Still, the agency required a new class warning and certain safety measures to be implemented. In its December 19, 2017, safety announcement, the FDA stated:9
“… after additional review and consultation with the Medical Imaging Drugs Advisory Committee, we are requiring several actions to alert health care professionals and patients about gadolinium retention after an MRI using a GBCA, and actions that can help minimize problems.
These include requiring a new patient Medication Guide, providing educational information that every patient will be asked to read before receiving a GBCA. We are also requiring manufacturers of GBCAs to conduct human and animal studies to further assess the safety of these contrast agents …
Health care professionals should consider the retention characteristics of each agent when choosing a GBCA for patients who may be at higher risk for gadolinium retention …
These patients include those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions. Minimize repeated GBCA imaging studies when possible, particularly closely spaced MRI studies.”
Patients Responsible for Requesting Medication Guide
However, while MRI centers are required to provide the gadolinium medication guide to all first-time patients scheduled for an enhanced MRI, hospital inpatients are not required to receive the guide unless the patient specifically requests it. A rather disconcerting detail mentioned in the FDA’s May 16, 2018, update is that:10
“A health care professional who determines that it is not in a patient’s best interest to receive a Medication Guide because of significant concerns about its effects may direct that it not be provided to that patient.”
In other words, if they think you might say no to the procedure because you’re worried about heavy metal toxicity, the health professional is allowed to simply withhold the safety information. Only if you specifically ask for it must that guide be provided to you.
While the FDA decided not to restrict the use of any GBCAs, the European Medicines Agency’s Pharmacovigilance and Risk Assessment Committee has recommended suspending the use of four linear gadolinium contrast agents shown to be less stable (and therefore more likely to accumulate in the brain and cause issues in those with kidney problems) than macrocyclic GBCAs.11
Most Radiologists Hide Findings of Gadolinium Deposits
An equally disturbing finding12 is that 58% of radiologists hide findings of gadolinium deposits from patients when they’re found on scans. As reported by Health Imaging,13 the most commonly cited justification for omitting any mention of gadolinium deposits in their radiology report was to avoid provoking “unnecessary patient anxiety.”
However, this also prevents patients from taking action to protect their health, which could be really important if they’re experiencing effects of gadolinium toxicity and haven’t put 2 and 2 together yet.
To date, the greatest danger of GBCA has been thought to be relegated to those with severe kidney disease, in whom GBCA exposure has been linked to nephrogenic systemic fibrosis (NSF),14 a debilitating disease involving progressive tissue fibrosis involving skin and subcutaneous tissues.15 To avoid this, those with kidney disease need to receive more stable forms of chelate with the gadolinium.16
However, the fact that gadolinium can accumulate in the brain (and throughout your body) even if you do not have kidney problems could have significant, hitherto unrecognized, dangers. For example, use of GBCAs has been linked to hypersensitivity in two brain regions (the dentate nucleus and globus pallidus),17 the consequences of which are still unknown.
Hyperintensity in the dentate nucleus has previously been linked to multiple sclerosis, and according to more recent research, this hyperintensity may actually be the result of the large number of enhanced MRI scans MS patients tend to receive.18 Hyperintensity of the globus pallidus, meanwhile, has been linked to liver dysfunction.
Researchers Propose New Gadolinium Disease Category
In the 2016 paper,19 “Gadolinium in Humans: A Family of Disorders,” the researchers actually propose that GBCA deposits in the body should be viewed as a new disease category. They write:
“In early 2014, an investigation by Kanda et.al. described the development of high signal intensity in brain tissue on T-2 weighted images of patients with normal renal function after repeated administrations of GBCA …
This caught many radiologists by surprise, as many had thought that deposition of gadolinium could not occur in patients with normal renal function. This deposition results in signal-intensity increase on unenhanced T1-weighted images in different regions of the brain, primarily in the dentate nucleus and globus pallidus …
To our knowledge, neither the bone deposition first reported by Gibby et. al. nor the brain deposition first reported by Kanda et. al. have been associated with recognized disease. We propose to name these storage entities ‘gadolinium storage condition.’
Along a separate avenue of inquiry, patient advocacy groups have formed, with an online presence in which individual members report that they have experienced severe disease following the administration of GBCAs.
Some of these patients have reported persistent presence of gadolinium in their systems, as shown by continued elevated gadolinium in their urine. All experience a variety of symptoms including pain in both the torso and the extremities; the latter location is associated with skin thickening and discoloration.
These physical features are similar, but lesser in severity, to those reported for NSF. Our preliminary investigation has convinced us that this phenomenon is a true disease process, which we propose naming ‘gadolinium deposition disease.'”
The researchers go on to note other common signs and symptoms of “gadolinium deposition disease,” such as persistent headache, bone, joint, tendon and ligament pain (often described as sharp pins and needles, cutting or burning), tightness in the hands and feet, brain fog and soft-tissue thickening that “clinically appears somewhat spongy or rubbery without the hardness and redness observed in NSF.”
Lawsuit Highlights Gadolinium Dangers
“Gadolinium deposition disease” is what Chuck Norris’ wife Gena claims to have developed after undergoing three contrast-enhanced MRIs in a single week to evaluate her rheumatoid arthritis.
The study cited above is part of the evidence included in the Norris’ lawsuit20,21 (filed in November 2017) against several manufacturers and distributors of GBCAs. According to the lawsuit, the risks of gadolinium were known, yet patients are not warned.
Gena’s symptoms began with a burning sensation in her skin. In a 2017 Full Measure interview, she described it as if there was acid burning her skin, slowly covering her body.22 Mental confusion, muscle spasms, kidney damage and muscle wasting followed.
She visited the emergency room several nights in a row, where doctors ran tests for ALS, MS, cancer and Parkinson’s disease. The couple’s attorney, Todd Walburg, told CBS News,23 “We have clients who have been misdiagnosed with Lyme disease, ALS, and then they’ve eventually ruled all those things out and the culprit remaining is the gadolinium.”
In fact, it was Gena who made the connection between her symptoms and the MRIs she had undergone. She told Full Measure:24
“When we got to the hospital in Houston this last time, and I’m so bad and I said, listen, I am sober enough in my thinking right now, because I had such brain issues going on, I said I’m only going to be able to tell you this one time and I need you to listen to me very closely. I have been poisoned with gadolinium or by gadolinium and we don’t have much time to figure out how to get this out of my body or I am going to die.”
The Norrises claim they’ve spent nearly $2 million on efforts to restore Gena’s health, with little progress. Even chelation therapy has had limited success.25
Heavy Metal Toxicity Is a Common Modern Hazard
Heavy metals are widely distributed throughout the environment from industrial, agricultural, medical and technical pollution. Heavy metal toxicity has documented potential for serious health consequences, including kidney, neurological, cardiovascular, skeletal and endocrine damage.
Heavy metals most commonly associated with poisoning are arsenic, lead, mercury and cadmium, which are also the heavy metals most commonly found in environmental pollution. Symptoms of heavy metal poisoning vary based on the organ systems affected.
Scientists have found that heavy metals also increase oxidative stress secondary to free radical formation.26 Testing for heavy metal toxicity includes blood, urine and hair and nail analysis for cumulative exposure.
The key take-home message here is to avoid using MRI scans with contrast unless absolutely necessary. Many times, physicians will order these tests just to be complete and cover themselves from a legal perspective.
If that is your case, then simply refuse to have the test done with contrast. If necessary, consult with other physicians that can provide you with a different perspective.
This is particularly important if you have a condition such as MS in which multiple MRIs are done. Also remember that multiple MRIs with contrast will be particularly dangerous the closer they’re done together.
If You Need an MRI, It Pays to Shop Around
While I always recommend being judicious in your use of medical diagnostic procedures, there are times when it is appropriate and useful for you to have a certain test.
What many don’t realize is that the fees for these procedures can vary tremendously, depending on where they are performed. Hospitals tend to be the most expensive option for diagnostics and outpatient procedures, sometimes by an enormous margin.
Freestanding diagnostic centers are alternative places to obtain services such as lab studies, X-rays and MRIs, often at a fraction of the cost charged by hospitals. Private imaging centers are not affiliated with any particular hospital and are typically open for Monday through Friday business hours, as opposed to hospital radiology centers that require round-the-clock staffing.
Hospitals often charge higher fees for their services to offset the costs of their 24/7 operations. Hospitals also may charge exorbitant fees for high-tech diagnostics, like MRIs, to subsidize other poorly reimbursed services. And, hospitals are allowed to charge Medicare and other third-party insurers a “facility fee,” leading to even more price inflation.
Neurodegenerative conditions are largely characterized by the aggregation of a few altered proteins that are prone to forming solid deposits in and around neurons. Tissues, such as the brain, made up of long-lived cells, such as neurons, are particularly vulnerable to this sort of dysfunction, as they cannot dilute harmful protein aggregates by cell division, and dysfunctional cells are not readily destroyed and replaced. Cells must rely upon internal quality control mechanisms such as the presence of chaperone proteins responsible for chasing down misfolded or otherwise problematic proteins, and ensuring they are refolded correctly or recycled via autophagy.
The quality control mechanisms of chaperone mediated autophagy are known to be important in aging. Increased autophagic activity is associated with many of the means of modestly slowing aging demonstrated in laboratory animals in past decades. Autophagy declines with age, and this is thought to be important in the development of neurodegenerative conditions precisely because neurons are heavily reliant on quality control to maintain function. Researchers are interested in finding ways to build therapies for age-related conditions based on upregulation of autophagic activity, and, as noted in today’s open access paper, the class of chaperone proteins called heat shock proteins are one prominent area of investigation.
Maintenance of cellular protein homeostasis (proteostasis) is crucial for cell function and survival. Neurons are particularly sensitive to dysregulated proteostasis as evidenced by the accumulation and aggregation of amyloidogenic proteins, which are a hallmark of neurodegenerative disease. Cellular molecular chaperone systems modulate proteostasis, and, therefore, are primed to influence aberrant protein-induced neurotoxicity and disease progression. Molecular chaperones have a wide range of functions from facilitating proper nascent folding and refolding to degradation or sequestration of misfolded substrates.
ATP-dependent chaperones, like the 70 kDa heat shock protein (Hsp70) and the 90 kDa heat shock protein (Hsp90), facilitate refolding, degradation, or sequestration of these misfolded proteins. Small heat shock proteins (sHsps) that lack an ATPase domain and are between 12 and 43 kDa are a class of molecular chaperones that typically associate early with misfolded proteins. These interactions hold proteins in a reversible state that helps facilitate refolding or degradation by other chaperones and co-factors.
Potential therapeutic strategies that aim to modulate endogenous sHsp expression or phosphorylation generally suffer from a lack of specificity for the sHsp family, let alone for discrete sHsps. Heat stress-responsive sHsps can be activated by drugs that generate a challenge to proteostasis, which includes proteasome inhibitors (e.g. Bortezomib), Hsp90 inhibitors (e.g. 17-AAG), and oxidative stress inducers (e.g. terrecyclic acid). However, these treatments also induce expression of other molecular chaperone families (e.g. Hsp70 and Hsp40) and are not specific for sHsp activation. Efforts to identify Hsp co-inducers, substances that potentiate stress responses without inducing a primary stress response on their own, may offer improved selectivity.
Small molecules that interact with sHsps may be a promising strategy for therapeutics, but the nature of this family of chaperones makes drugability difficult. There are no known small molecule ligands to use as a scaffold to start from. The dynamic nature of these proteins taunt the idea of engineering a high affinity binding drug; indeed, these promiscuous proteins likely have many client binding sites with a variety of conformations.
The diversity of sHsps from different organisms, from bacteria to humans, provides a rich set of proteins to explore for aggregation prevention activity. For example, a sHsp from a parasite was shown to be a potent inhibitor of amyloid-βfibrillation and reduced associated toxicity in a neuroblastoma cell model. Specific mutant or engineered sHsp variants, with altered oligomeric structure or client interactions, may prove to have increased chaperone activity towards amyloidogenic proteins. Small peptides derived from human HspB4 and HspB5 sequences, termed mini-chaperones, display chaperone-like activity. One of these constructs reduced cellular toxicity of amyloid-β.
Today’s open access paper discusses possible approaches to the treatment of immunosenescence, the age-related decline in effectiveness of the immune system. Unfortunately it is largely a tour of compensatory treatments, ways to force the cells of the immune system into greater or more useful activity without addressing any of the underlying causes of immunosenescence. Many of these methodologies have serious side-effects, are disruptive of normal immune function and overall health, and cannot be applied for the long term. Checkpoint inhibition, or the delivery of recombinant IL-7, for example, both of which are used as short term interventions to treat cancer.
The one approach outlined at length in this open access paper that does address a plausible cause of immunosenescence is vaccination against cytomegalovirus (CMV). Near everyone is silently infected by late life, and the adaptive immune system becomes ever more devoted to trying and failing to clear this persistent viral infection. Ever more T cells are specialized to CMV, leaving ever fewer available for other tasks. As the supply of new T cells diminishes with age, this overspecialization becomes a serious issue, contributing greatly to the decline in immune function.
The authors here make the point that all of the necessary knowledge and technology already exists to put together a viable, widely used vaccine for CMV, but the will to do so is absent. We live in a world in which HPV vaccination became a reality, however, and CMV is arguably far worse when it comes to costs and suffering. Perhaps, at some point in the years ahead, the slow machineries of regulation will come to the point at which people are regularly vaccinated against CMV in order to reduce the impact of aging on immune function. I think it likely that selective destruction of CMV-specialized immune cells is more likely to emerge as a branch of therapy before that happens, however.
Until a few decades ago, a very small fraction of the population would reach 80 years of age. Now this is a frequent event, with the average life expectancy for a newborn to have risen to 80 years in most Western European countries. However, the increase in lifespan does not coincide with increase in healthspan. The link between aging and disease is in part a reflection of the functional changes in the immune system of older people. Different factors contribute to the development of age-related immune dysfunction, but the epilog of an aged immune system is an increased propensity toward a reduced resistance to infection, poorer responses to vaccination, and the development of age-related diseases.
The analysis of the contributing factors to this profound immune remodeling has revealed a complex network of alterations that influence both innate and adaptive arms of the immune system. The diversity of cells, molecules and pathways involved in this remodeling, and their ability to influence each other, including the intra- and inter-individual variability of the immune response, make it hard to identify interventions that can be predicted to improve or, at least, to maintain the immune function in older adults. Within the past few years, numerous studies of the underlying mechanisms of age-related immune decline have laid the groundwork for the identification of targeted approaches, focusing on interventions able to target the hallmarks of immunosenescence.
Taking into account the role of HCMV in the decrease of naïve T cells and increase of memory T cells, the reduction of the latent/lytic viral load, by vaccination and/or antiviral drugs, should be beneficial to diminish HCMV-associated immunosenescence. As a result of 40 years of work, there are many candidate HCMV vaccines. Therefore, we know the antigens needed in a HCMV vaccine, and that vaccination can be protective. To reach the goal of an effective HCMV vaccine, now we need a concentrated effort to combine the important antigens and to generate durable responses that will protect for a significant period.
It is well established that exercise and physical fitness correlate well with reduced incidence of all of the common age-related diseases, and reduced mortality risk. It is hard to establish causation from the contents of human epidemiological databases, but the analogous animal studies convincingly demonstrate that exercise improves health. There is no reason to expect humans to be all that different in this matter. Here, researchers show that, much as expected, greater fitness correlates with reduced risk of dementia. Of note, patients that improved their fitness over the years of later life exhibited reduced disease risk and improved life expectancy.
Cardiorespiratory fitness is associated with risk of dementia, but whether temporal changes in cardiorespiratory fitness influence the risk of dementia incidence and mortality is still unknown. We aimed to study whether change in estimated cardiorespiratory fitness over time is associated with change in risk of incident dementia, dementia-related mortality, time of onset dementia, and longevity after diagnosis in healthy men and women at baseline. We linked data from the prospective Nord-Trøndelag Health Study (HUNT) with dementia data from the Health and Memory Study and cause of death registries (n=30,375). Included participants were apparently healthy individuals for whom data were available on estimated cardiorespiratory fitness and important confounding factors.
Cardiorespiratory fitness was estimated on two occasions 10 years apart, during HUNT1 (1984-86) and HUNT2 (1995-97). HUNT2 was used as the baseline for follow-up. Participants were classified into two sex-specific estimated cardiorespiratory fitness groups according to their age (10-year categories): unfit (least fit 20% of participants) and fit (most fit 80% of participants). To assess the association between change in estimated cardiorespiratory fitness and dementia, we used four categories of change: unfit at both HUNT1 and HUNT2, unfit at HUNT1 and fit at HUNT2, fit at HUNT1 and unfit at HUNT2, fit at both HUNT1 and HUNT2. Using Cox proportional hazard analyses, we estimated adjusted hazard ratios (AHR) for dementia incidence and mortality related to temporal changes in estimated cardiorespiratory fitness.
During a median follow-up of 19.6 years for mortality, and 7.6 years for incidence, there were 814 dementia-related deaths, and 320 incident dementia cases. Compared with participants who were unfit at both assessments, participants who sustained high estimated cardiorespiratory fitness had a reduced risk of incident dementia (AHR 0.60) and a reduced risk of dementia mortality (AHR 0.56). Participants who had an increased estimated cardiorespiratory fitness over time had a reduced risk of incident dementia (adjusted hazard ratio 0.52) and dementia mortality (adjusted hazard ratio 0.72) when compared with those who remained unfit at both assessments. Each metabolic equivalent of task increase in estimated cardiorespiratory fitness was associated with a risk reduction of incident dementia (AHR 0.84) and dementia mortality (AHR 0.90). Participants who increased their estimated cardiorespiratory fitness over time gained 2.2 dementia-free years, and 2.7 years of life when compared with those who remained unfit at both assessments.
There is no consensus in science that is so strong as to have no heretics. So here we have an interview with a naysayer on the matter of senolytic treatments, who argues that the loss of senescent cells in aged tissues will cause more harm to long-term health than the damage they will do by remaining. To be clear, I think this to be a ridiculous argument given the present evidence. To make it one has to declare the existing results showing extension of healthy life span in mice to be something other than credible data, which just isn’t the case. Further, it seems shaky on theoretical grounds to suggest that removal of something like 1% of cells will put onerous stress on the remaining 99%, particularly given that the 1% were contributing to declining stem cell activity via inflammatory signaling. All told, it is hard to take seriously the idea that loss of senescent cells can possibly produce greater degrees of dysfunction in tissue than is caused by the inflammatory signaling of senescent cells.
Your new review on senolytics suggests that senolytics may cause more harm than good. Can you summarize your objections and concerns?
Here is the argument: 1) theoretically, senolytics should make things worse and 2) the available data support this theoretical concern. To use an analogy, imagine that you have a factory in which 10 of the 100 factory workers are feeling overworked and tired. Furthermore, their complaints are disrupting the other workers. You have two possible interventions. You can: (a) Fire the 10 workers, thereby removing the complainers. The result is that the remaining 90 workers are now overworked, and they, too, begin to complain. You end up with 30 workers who are now complaining and disrupting your factory. This is the senolytic approach. (b) Improve the health and conditions of the 10 workers who are overworked and complaining. You now have 100 workers who are doing an excellent job. This is the telomerase therapy approach.
In the first case, your factory has a problem and you make it worse. In the second case, your factory has a problem and you solve the problem. This figure from my new paper illustrates the same point in terms of nine cells subjected to senolytics, with the result being temporary short-term improvement followed by decline and a worse situation than we started with.
This does not take into account the idea of replacing that pool of “workers” by bringing in fresh stem cells.
You have to keep a few points in mind. 1) Will the stem cells populate as desired? 2) If you do get a stem cell population, that requires cell division, which shortens telomeres, which accelerates cell senescence, and once again you have accelerated pathology. 3) Why would you bother recruiting stem cells when you can much more easily reset cell senescence in the resident cells of the tissue? 4) The long-term data (what there is of it) supports the failure of senolytics. Again: remember where those “new cells” come from: you are accelerating senescence in the stem cell pool. The only way to “replace them with healthy working cells” is to simply and effectively reset gene expression, taking senescing cells and turning them into functionally young cells.
It seems that we can only speculate on these issues, as these long-term follow-ups have not yet been done. However, senolytics have been shown to increase median lifespan and healthspan in murine models.
I don’t see any credible data that supports the contention that “senolytics have been shown to increase median lifespan and healthspan in murine models”.