Mitochondrial Ion Channels in the Mitochondrial Dysfunction that Occurs with Aging

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Mitochondria are the power plants of the cell, present by the hundred in near every cell type in the body. They are important in many fundamental cellular processes, but their primary task is to package chemical energy stores in the form of adenosine triphosphate (ATP). Mitochondrial function declines with age in all tissues, and this is particularly problematic in energy-hungry tissues such as the brain and muscles. The cause of this decline may be failure of the quality control mechanisms of mitophagy, responsible for dismantling damaged mitochondria, or it may have deeper roots, such as loss of capacity for mitochondrial fission. Until some of those possible roots can be fixed reliably, it will be hard to assign relative importance to their contributions.

Given that mitochondrial function declines across the board, it will not be surprising to find that any given mechanism exhibits problems in older individuals. Mitochondria are wrapped in membranes, and those membranes use ion channels to pass various ions essential to their operation, such as calcium, back and forth. The open access paper here examines age-related mitochondrial dysfunction through the lens of ion channels and disruption of their activity. This seems likely a downstream issue, but as ever it is quite hard to determine cause and consequence in the mechanisms associated with aging without the ability to reliably intervene to fix just one thing in isolation.

Mitochondria are often referred to as the powerhouse of the cell, however, their physiological role goes well beyond that Mitochondria are highly dynamic organelles regulating their structure in line with metabolism, redox signaling, mitochondrial DNA maintenance, and apoptosis. Besides from generating adenosine triphosphate (ATP) for cellular energy, mitochondria are also deeply involved in providing intermediates for cellular signaling and proliferation. Mitochondria can alter their size and organization as a result of mitochondrial fission and fusion in response to various intracellular and extracellular signals. Fission and fusion events occur to meet metabolic demands and for the removal of damaged/dysfunction mitochondria. The role of mitochondrial fission and fusion in facilitating metabolism has been researched extensively. Fused mitochondrial networks typically engage more oxidative pathways of metabolism, whilst fragmentation as a result of stress impairs the oxidative pathway and increases cellular demand on glycolysis.

Ion channels are intimately involved in regulating mitochondrial function. The essential role of cationic hydrogen (H+) ion transfer in ATP production was noted as early as 1961. H+ ions are pumped from the mitochondrial matrix into the intermembrane space by the flow of electrons through the electron transport chain. These ions are then utilized to drive the ATPase machinery and phosphorylate ATP, thus creating energy for the cell. The movement of ions across the mitochondrial membrane is also essential in establishing membrane potential and maintaining proton (H+) flux. Ions transported across the inner membrane include potassium (K+), sodium (Na+) and calcium (Ca2+), alongside H+. The most well-studied ion channel within the mitochondrion is the voltage-dependent anion channel, VDAC, which is the primary route of metabolite and ion exchange across the outer mitochondrial membrane.

Mitochondrial channelopathies have been found in aging, affecting the K+, Ca2+, VDAC and permeability transition pore (Ca2+; PTP) channels. Mitochondrial Ca2+ cycling is impaired with aging in neurons, resulting from reduced Ca2+ channel activity and reduced recovery after synaptosomal stimulation. This reduced calcium recovery rate results in reduced mitochondrial membrane potential and delayed repolarization, causing mitochondrial dysfunction with aging. This effect has been found in the heart of 2 year old senescent rats. In terms of potassium channels, it has been shown that their density on the surface of mitochondria significantly declines with age and with metabolic syndromes in the heart sarcolemma. This has been shown to reduce tolerance to ischemia-reperfusion and increased injury in aged guinea pig and rat hearts, and also humans.

These effects have repercussions in increasing susceptibility to myocardial infarction and reducing neuronal activity in the elderly as mitochondrial K+ channels have been shown to play a neuroprotective role in neurological reperfusion injury in postnatal mouse pups. Amyloid-β plaques in Alzheimer’s disease have been shown to increase intracellular calcium levels. This increase in intracellular calcium, and uptake into the mitochondria through the VDAC and calcium uniporter, has been shown to increase mitochondrial stress responses and initiate apoptosis in rat cortical neurons in vitro and hippocampal slices ex vivo. Recent studies in Parkinson’s disease, have revealed that α-synuclein acts via the VDAC to promote mitochondrial toxicity of respiratory chain components in a yeast model of Parkinson’s.


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Low Mitochondrial Permeability is Required for Autophagy to Extend Life Span

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Mitochondria are the power plants of the cell, generating the chemical energy store molecule adenosine triphosphate (ATP) that powers cellular processes. Every cell possesses a herd of mitochondria, replicating like bacteria, and monitored by quality control mechanisms. Damaged, potentially harmful mitochondria are removed and dismantled for raw materials through a variant of autophagy called mitophagy. A mountain of evidence links mitochondrial function to aging, just as a mountain of evidence links the cellular recycling mechanisms of autophagy to aging. Both mitochondrial function and autophagic activity decline with age, producing downstream consequences that contribute to age-related diseases. There is the strong suspicion, with evidence to back it up, that it is the quality control of mitochondria, and thus maintenance of mitochondrial function without harmful side-effects resulting from damaged mitochondria, that is the common factor here.

Enhanced autophagy is a feature common to many of the methods by which aging can be slowed and life span extended in short-lived laboratory species. Most of these work via upregulation of cellular stress responses – to heat, lack of nutrients, oxidative damage, and so forth – and autophagy is an important stress response mechanism, making cells more resilient. Minor or short stresses lead to a longer upregulation of the response to stress, and thus the overall result is an improvement in health and longevity. This is called hormesis, and is a major part of the way in which intermittent fasting or calorie restriction work. Researchers have in the past demonstrated that calorie restriction actually fails to extend life in animals in which autophagy is disabled.

The topic for today is specifically the permeability of the mitochondrial membrane and its role in the relationship between mitochondrial function and autophagy. A fair amount of attention has been directed in recent years towards the mitochondrial permeability transition pore structures in the mitochondrial membrane, and their role in mitochondrial dysfunction. Clearly greater pore activity and thus greater permeability are a feature of aging, alongside mitochondrial dysfunction, but joining the dots on what is cause and what is consequence in our biochemistry is far from simple. It is known that mitophagy falters in later life, and it is known that this appears to be at least partly a consequence of reduced levels of mitochondrial fission – but consider how long it took to join just those two items. Why do mitochondrial fission rates fall? How does that relate to permeability and the membrane structures that support it? The complexity is overwhelming, which is perhaps why the path forward towards near term therapies is usually to cut the Gordian knot in some way, bypass the system that is poorly understood. Many of the SENS-style proposed rejuvenation therapies based on repair of underlying damage are of this form.

Mitochondrial permeability plays a key role in aging, recovery from ischemic injury

The ability of molecules to pass through the membrane of mitochondria – the cellular structures that convert nutrients into energy – may determine whether or not autophagy, a cellular process that removes damaged and dysfunctional molecules and cellular components, is beneficial or detrimental to the health of an organism. As the accumulation of damaged molecules and defective proteins is considered a hallmark of aging, autophagy has been associated with increased longevity. In fact, model organisms in which gene mutations or measures such as calorie restriction lead to lifespan extension depend on autophagy for their beneficial effects. However, autophagy can also play a role in cancer, diabetes, neurodegeneration and in the ischemia/reperfusion injury caused by restricted blood flow.

Previous studies have suggested that inhibition of the mTORC2 molecular pathway, which controls several critical metabolic functions, shortens lifespan. Organisms in which mutations in mTORC2 or in the gene encoding its downstream effector protein SGK-1 have reduced lifespan also show increased autophagy. Experiments revealed that inhibition of autophagy can restore a normal lifespan in mTORC2/SGK1 mutant C. elegans roundworms. The researchers also found that SGK-1 can regulate the opening of the mitochondrial permeability transition pore (mPTP), which allows very small molecules to pass through the mitochondrial membrane. Excessive opening of the mPTP, either by inhibition of the mTORC2/SGK-1 pathway or by direct genetic stimulation, transforms autophagy from a beneficial to a detrimental function, resulting in a shortened lifespan. Overall, the results indicate that the beneficial effects of autophagy depend on low levels of mitochondrial permeability.

Since autophagy is believed to contribute to ischemic injury, the investigators looked at its potential role in ischemia/reperfusion (I/R) injury – the exacerbation of tissue damage that occurs when blood flow is restored to tissue to which it had been restricted. They found that mice in which expression of the gene for SGK-1 was knocked out in the liver were more susceptible to I/R injury of the liver than were unmutated animals. While both current and previous research has indicated that elevated autophagy and mitochondrial permeability are harmful in the early phases of reperfusion injury, autophagy may help reduce the severity of tissue damage at later stages when damaged cellular components must be cleared from the cell.

Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension

Autophagy is required in diverse paradigms of lifespan extension, leading to the prevailing notion that autophagy is beneficial for longevity. However, why autophagy is harmful in certain contexts remains unexplained. Here, we show that mitochondrial permeability defines the impact of autophagy on aging. Elevated autophagy unexpectedly shortens lifespan in C. elegans lacking serum/glucocorticoid regulated kinase-1 (sgk-1) because of increased mitochondrial permeability. In sgk-1 mutants, reducing levels of autophagy or mitochondrial permeability transition pore (mPTP) opening restores normal lifespan.

Remarkably, low mitochondrial permeability is required across all paradigms examined of autophagy-dependent lifespan extension. Genetically induced mPTP opening blocks autophagy-dependent lifespan extension resulting from caloric restriction or loss of germline stem cells. Mitochondrial permeability similarly transforms autophagy into a destructive force in mammals, as liver-specific Sgk knockout mice demonstrate marked enhancement of hepatocyte autophagy, mPTP opening, and death with ischemia/reperfusion injury. Targeting mitochondrial permeability may maximize benefits of autophagy in aging.

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A Study Observing No Significant Relationship Between Exceptional Longevity and Cardiovascular Risk Factors

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Today’s open access paper illustrates one of the many issues inherent in the study of the biochemistry and genetics of exceptionally long-lived people, which is that the data from various different initiatives rarely agrees. The effects of individual or even groups of gene variants are small and hard to pin down. Past studies have suggested that exceptional longevity is correlated with a lack of cardiovascular risk factors, whether genetic or measured aspects of biochemistry such as lipid levels in blood. That seems a sensible hypothesis: cardiovascular disease removes people from the population, therefore older cohorts should exhibit fewer signs of risk for cardiovascular disease. Yet that is not the case in the work presented here: there is no good association between longevity and lesser presence of risk factors.

What this sort of distribution of results should tell us is that the biochemistry of exceptional human longevity is a poor area of study if the goal is to produce reliable therapies with large effects on human aging. Old people who survive to very late life do so largely because they are either lucky (in exposure to pathogens, in the way in which the damage of aging progressed in a stochastic manner in their case) or because they made good lifestyle choices for much of their span of years. Or both. Beneficial genetic variants and consequent differences in cellular metabolism appear to confer only very modest increases in the odds of living for a long time, and even for those people who do live longer, the impact of degenerative aging is very significant. An environment of small, unreliable effects should be skipped in favor of research strategies with larger potential gains at the end of the day.

Exceptional Longevity and Polygenic Risk for Cardiovascular Health

Exceptional longevity, defined as exceeding the average life expectancy, is multifaceted with genetic, environmental, and epigenetic factors all playing a role. Exceptionally long-lived (ELL) individuals are examples of successful ageing with a proportion demonstrating compression of morbidity. It is important to study these models of successful ageing, as these rare individuals may reveal novel longevity-associated pathways, which may ultimately translate into strategies to promote health in our ageing population.

There is evidence linking healthier cardiovascular risk profiles and lower incidence of cardiovascular disease with longevity. Analysis of lipid metabolism in longevous families identified changes in lipid concentration in the offspring of nonagenarians. Levels of apolipoproteins, important lipid transporters in the circulatory system, have been observed to decline with age. However, higher apolipoprotein levels in the exceptionally long lived have been reported, suggesting a younger apolipoprotein profile that may promote longevity.

Polygenic risk scores (PRS) for cardiovascular-related phenotypes can now be calculated due to the availability of summary data from genome-wide association studies (GWAS) examining a broad range of traits from lipids to coronary artery disease. This facilitates the evaluation of the contribution of polygenic risk for cardiovascular risk factors and disease to exceptional longevity and successful ageing. Thus, the purpose of this study was to explore the genetic profiles of ELL individuals aged (≥95 years) by assessing their polygenic risk for cardiovascular related risk and disease phenotypes relative to middle-aged controls.

This study did not confirm the hypothesis that ELL individuals have lower polygenic risk scores for cardiovascular-related phenotypes. Only the HDL cholesterol and triglyceride PRS were nominally significantly associated with ELL participants. In contrast and as expected, ELL individuals had higher polygenic risk scores for exceptional longevity (EL). In regards to the associations of the various cardiovascular PRS with EL, no findings survived correction for multiple testing. This is despite validating the utility of the lipid PRS by confirming positive associations with measured lipid levels in our sample. Interestingly, the different lipid PRS were based on GWAS that found a large number of genome-wide significant loci. ELL individuals had lower LDL and total cholesterol levels than controls in this study, but they did not differ on their respective PRS. This may suggest that environmental factors, perhaps lifestyle-related, influenced these lipid levels, which possibly promote longevity.

In contrast, the UK Biobank study observed that extreme parental longevity (defined as at least one parent who survived to the top 1% of age at death) had lower polygenic risk for several cardiovascular health measures. Namely coronary artery disease, systolic blood pressure, body mass index, high-density lipoproteins, low-density lipoproteins, and triglycerides. A similar result for HDL cholesterol and extreme parental longevity (EPL) by the UK Biobank to the current study was reported. Again, similar results were reported by the UK Biobank for LDL. However, the observed discrepancies between our analysis and the UK Biobank were most likely due to methodological differences, including the use of PRS that were based on different GWAS.

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There is a Large Difference in Mortality Rate Between a Sedentary Lifestyle and Daily Physical Activity

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Exercise, like all interventions that improve health, has a dose-response curve. As in most such curves, the initial difference between no treatment (a sedentary or near-sedentary lifestyle) and some treatment (moderate physical activity every day) is quite large. Further increments in activity can add increasing benefits, but ever less as activity time increases further. There is an optimal point at which one can be fairly certain of capturing most of the benefits, even given the usual uncertainties in measurement and variation in the response of individuals. For aerobic exercise, and the average human being, the optimal point is probably a greater amount of time than the 30 minutes daily presently recommended.

Regular moderate- to vigorous-intensity physical activity (MVPA) is associated with a lower risk of cardiovascular disease; certain cancers; and premature death. In addition, the amount of time spent sedentary – distinct from physical inactivity – is associated with a higher risk of death and disease. That may be a result, at least in part, from sedentary behavior displacing physical activity.

Most previous studies have explored the potential effect of sedentary time without considering the physical activity it displaces, leaving a gap in the understanding of the issue. To explore further, investigators analyzed self-reported sitting time, light physical activity, and moderate/vigorous physical activity among 92,541 participants in the ACS’s Cancer Prevention Study II Nutrition Cohort.

The analysis reviewed sedentary time and activity levels over 14 years. It found among those who were the least active at baseline (less than 17 minutes/day moderate to vigorous physical activity), replacing 30 minutes/day of sitting with light physical activity was associated with a 14% reduced risk of death, while replacement with moderate to vigorous physical activity was associated with a 45% reduced risk of death.

The investigators found similar but smaller associations among moderately active participants: replacing a half hour of sedentary time with light physical activity was associated with a 6% reduction in mortality among those who were moderately active; replacing 30 minutes of sitting time with moderate to vigorous physical activity was associated with a 17% mortality reduction in this group. However, for the most active (more than 38 minutes/day of MVPA), substitution of sitting time with light physical activity or MVPA was not associated with a reduction in mortality risk.


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CBX4 Upregulation Reduces Cellular Senescence and Osteoarthritis in Mice

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Cellular senescence is one of the causes of aging; the inflammatory signals generated by growing numbers of senescent cells disrupt tissue maintenance and cell function, and play an important role in many age-related conditions, including osteoarthritis. The best approach to senescent cells appears to be the simple one: destroy them. They accumulate slowly, and therapies that selectively remove senescent cells have been shown in animal studies to produce significant reversal of numerous aspects of aging. Nonetheless, many research groups are more interested in preventing or modulating senescence, with the open access paper here an example of the former. To my eyes, therapies that have to be taken over decades to slow the accumulation of senescent cells are a very poor second best to methods of immediate clearance of these cells.

Stem cell senescence contributes to stem cell exhaustion, a major cause of physiological and pathological aging. Mesenchymal stem cells (MSCs) are adult multipotent cells in various mesodermal tissues that are capable of differentiating into mature cells such as osteoblasts, chondrocytes, and adipocytes. Both physiologically aged individuals and patients with premature aging syndromes exhibit functional degeneration in mesodermal tissues, along with exhaustion of MSC populations, thus characterized by atherosclerosis, osteoporosis, osteoarthritis, etc.

CBX4, a component of polycomb repressive complex 1 (PRC1), plays important roles in the maintenance of cell identity and organ development through gene silencing. However, whether CBX4 regulates human stem cell homeostasis remains unclear. In this study, we reported that CBX4 was downregulated during human MSC (hMSC) senescence and accordingly investigated the role of CBX4 in maintaining cellular homeostasis in hMSCs. Targeted CBX4 depletion in hMSCs resulted in loss of nucleolar heterochromatin, enhanced ribosome biogenesis, increased protein synthesis, and accelerated cellular aging. CBX4 overexpression alleviated senescent phenotypes in both physiologically and pathologically aged hMSCs.

More importantly, lentiviral vector-mediated CBX4 overexpression attenuated the development of osteoarthritis in mice. We demonstrate that CBX4 safeguards hMSCs against cellular senescence through the regulation of nucleolar architecture and function, suggesting a target for therapeutic interventions against aging-associated disorders.


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Outgoing Commissioner Unloads About Marlboro Vaping Lies

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The Marlboro brand owns nearly 40 percent of the cigarette market share.1 Marlboro is owned by Philip Morris, which in turn is owned by Altria. Altria also owns U.S. Smokeless Tobacco, makers of Copenhagen and Skoal chewing tobacco. In December 2018, Altria announced a $12.8 billion investment in Juul Laboratories, in exchange for 35 percent ownership in the company.

The acquisition also promised Juul services to accelerate the mission of the e-cigarette (e-cigs) company.2 With a declared mission to change “the lives of the world’s 1 billion adult smokers by eliminating cigarettes” and develop Juul to be “a satisfying alternative to cigarettes,”3 it may come as no surprise the company has garnered the vast majority of the e-cigarette market.4

Unfortunately, this is being achieved on the backs of children, the tobacco industry’s prime target market. If you have an addictive product, the best markets are those who will purchase it longer — or those with the longest life expectancy.

In other words, it costs more to acquire a customer who is 65 and may smoke for 15 years, as opposed to a 15-year old-who may smoke for 40 years before succumbing to an early death.

The rising number of children using e-cig vaping devices, especially the USB-shaped Juul products filled with fruit and candy flavored nicotine liquid, has been the focus of Scott Gottlieb since becoming the U.S. Food and Drug Administration (FDA) Commissioner in 2017.5 As he prepares to resign, Gottlieb expressed anger at how the industry has continued its long career of lying.

Rising Rates in Tobacco Target Market Trigger Threats From FDA Commissioner

At a recent meeting at the Brookings Institution,6 Gottlieb described how Altria, one of the world’s largest producers of tobacco products, including brands like Philip Morris, U.S. Smokeless Tobacco and John Middleton, went back on their promise to withdraw pod-based products from the market.

In a 15-page response to the Commissioner’s7 plan to address the vaping epidemic, Altria promised to hold pod-based sales for FDA approval. They withdrew some of their products but then acquired Juul months later in a $12.8 billion investment. Gottlieb commented at Brookings, saying:8

“It was a difficult meeting … It concerned me that a company that affirmed what we believe, which is that the pod-based flavored products are driving youth use, went so far as to take the product off the market and publicly make that statement … then made a substantial investment that also guaranteed that they’re going to expand the market share of the leading pod-based flavored products that’d been used by children.

There seems to be a disconnect. I assume it’s just a business decision they made to withdraw a product that didn’t have good market penetration and go on to make an investment in a similar product that did have the market penetration.”

Data from the Centers for Disease Control and Prevention’s (CDC) National Youth Tobacco Survey9 show there are 3.6 million middle and high school students who currently vape, over 1.5 million more than last year.10 The meteoric rise of vaping has overshadowed tobacco use in teenagers, escalating by 900 percent from 2011 to 2015.11

In the age group of 18- to 20-year-olds, 40 percent had not been smokers before using a vaping device. Morgan Stanley analyst Pamela Kaufman told investors,12 “Juul’s success underscores the potential for disruptive technology to undermine U.S. tobacco’s reliable business algorithm.” With the rising number of youth using Juul devices and then transitioning to traditional cigarettes, Gottlieb warns:13

“You’re going to be at overall tobacco use among children in this country, of 40, 45 percent … That is simply intolerable. I went back and looked at data back to 1950, and we haven’t seen that level of tobacco use among kids. And e-cigarettes are a tobacco product.”

Tobacco Industry’s History of Lies and Deceit Documented in Court

Beginning with what Bloomberg14 characterized as a “cautious approach,” the FDA attempted to ease regulations on the e-cigarette industry in 2017 to “encourage development of more products that could help adults quit smoking.”

However, this move didn’t do enough to prevent children from purchasing e-cig products like Juul, who reportedly owns over 75 percent of the market.15 Sidestepping the issue of selling flavored nicotine pods to teenagers is just the last in a long series of lies the tobacco industry has been telling for decades.

In 1999, the U.S. Government16 sued several large tobacco companies, including Philip Morris, now owned by Altria. For many years the tobacco industry understood the dangers to a person’s health and yet continued to sell the public on the idea that smoking was safe.

In the same lawsuit, it was claimed cigarette advertising to children younger than 21 was aimed at getting a new generation addicted to nicotine,17 to ensure new customers would replace those who died.18 In 2006, a judge found the tobacco company violated civil racketeering laws and ordered them to tell the truth in paid advertising.19

The industry delayed the court order for over 11 years and now has been forced to publish corrective statements that should appear in 50 newspapers and on major broadcast networks.20

A large challenge is most teens do not see ads in newspapers or television any longer as they consume most of their news and entertainment online. According to U.S. District Judge Gladys Kessler, examples of how the industry misled the public include:21

  • Tobacco companies falsely denied they can and do manipulate the level of nicotine in their products to create and sustain addiction, and have been since at least 1954.
  • Tobacco companies “falsely denied, distorted and minimized” the link between cigarette smoking and disease, even though they internally recognized its existence.
  • Tobacco companies concealed evidence and publicly denied nicotine is addictive.
  • Tobacco companies “falsely marketed and promoted low-tar and light cigarettes as less harmful” than regular cigarettes to keep people smoking and sustain revenues.
  • Tobacco companies internally acknowledged secondhand smoke is hazardous to nonsmokers, yet still gave false and misleading public statements denying the fact.

Altria Holds to the Letter of Their Promise but Not the Intent

In the words of Truth Initiative, the court ruled the companies22 “systematically defrauded the American people by lying for decades about, among other things, the health effects of smoking and their marketing to children.”

According to Altria,23 “Our companies include some of the most enduring names in American business …” Despite a long and lurid history of lies and deceit, the FDA believed this zebra had changed its stripes when Altria promised to remove flavored pods from the market.

Holding true to the letter of their promise, they removed pods from some existing companies, but defied the spirit of intent when they invested in Juul to take advantage of Juul’s market value and lend Altria’s asset distribution channels to Juul.

Juul Seeking Expansion in the European Union

Even though the tobacco industry was found guilty of civil racketeering and deliberately addicting their consumer base to a product they knew would ultimately cause their death, Juul has been working to develop a product to get around the European Union (EU) rules regulating the amount of nicotine delivery in e-cigarettes.24

They reportedly hope to develop a pod with lower nicotine, but increase the voltage in the device to essentially deliver a similar “hit,” as they seek to expand their market in the EU. This is yet another demonstration of the tobacco industry’s desire to circumvent the law and its lack of regard for consumer safety.

Additionally, research has found exposure to nicotine during teen years may increase the risk of addictive behavior. Researchers25 used an animal model to evaluate if rats exposed to nicotine during adolescence would grow up to drink more alcohol than those who were not exposed. They discovered exposure changes the neurological circuitry in the brain within the reward pathway.

During adulthood this function did not change in the same way it does during adolescence. The alterations in neurotransmitters are responsible for sending signals during stress, or recognizing reward. Long-term changes in the midbrain reward center may also be a gateway to other addictive drugs, such as cocaine, heroin and morphine.26

Gottlieb supports the proposed rule to cut nicotine in cigarettes to nonaddictive levels as it may cause up to 5 million adults to quit smoking within the first year after the regulation is enacted.27

City Takes Matters Into Its Own Hands

In a unique moved to protect the citizens in their city, San Francisco officials are seeking to crack down on Juul and other e-cig manufacturers. Legislation has been proposed to ban the sale of e-cigarettes within the city limits and prohibit e-cigarette companies from occupying city-owned property in the future.28

The bills’ authors are city attorney Dennis Herrera and supervisor Shamann Walton in a district that includes Juul’s corporate headquarters. This proposal is part of several actions the city is undertaking. San Francisco already bans candy- and fruit-flavored tobacco products. Voters passed that bill in 2018.

The proposed bill to ban companies selling, manufacturing or distributing tobacco products from city owned property would not be retroactive. This means Juul would maintain its current office space but would be prevented from selling within the city limits. Herrera said:29

“These companies may hide behind the veneer of harm reduction, but let’s be clear, their product is addiction. They’re in the business of getting people addicted, or keeping them addicted.”

Juul has efficiently overtaken the e-cig market with a product that effectively delivers more nicotine. To read more on how Juul’s technology has made their pens more addictive than regular nicotine e-cig pods, see my previous article, “Why the New Nicotine is Super Addictive.”

Vaping Linked to Depression and Heart Attacks

Recent research reveals vaping is taking a large toll on health, and researchers say switching to e-cigarettes is not eliminating any health risks. Data was gathered in one of the largest-ever studies conducted on the health effects of vaping to be presented at the American College of Cardiology 68th Annual Scientific Session in New Orleans.30

The research reveals adults using e-cigarettes have a significantly higher chance of myocardial infarction, coronary artery disease and depression. Previous research has been mixed, with tobacco companies advertising e-cigs as a method to help traditional smokers kick the habit.31

However, these authors compared those who do not smoke against adults who vape and found those who smoke e-cigs were 56 percent more likely to have a heart attack and 30 percent more likely to suffer a stroke.32 They were also 55 percent more likely than nonusers to suffer from depression or anxiety.

Digging deeply into the data, researchers discovered the risk rose with vaping, despite the measured frequency. Dr. Mohinder Vindhyal, assistant professor at the University of Kansas School of Medicine, Wichita, and the study’s lead author, commented on the results:33

“Until now, little has been known about cardiovascular events relative to e-cigarette use. These data are a real wake-up call and should prompt more action and awareness about the dangers of e-cigarettes. When the risk of heart attack increases by as much as 55 percent among e-cigarettes users compared to nonsmokers, I wouldn’t want any of my patients nor my family members to vape.

When we dug deeper, we found that regardless of how frequently someone uses e-cigarettes, daily or just on some days, they are still more likely to have a heart attack or coronary artery disease.”

Avoid using e-cigarettes and seek other options to help you quit smoking. In my previous article, “Vaping Shuts Off Protective Cells in Your Lungs,” I share strategies to help make quitting smoking easier.

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Nicotinamide Riboside Reverses Age-Related Decline in Intestinal Stem Cell Populations

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Nicotinamide riboside supplementation is one of the ways to increase levels of NAD+ in mitochondria, thus improving mitochondrial function. This probably does little for young people, particularly young and physically fit people, but in old age NAD+ levels decline along with mitochondrial function. Mitochondria are the power plants of the cell, and with aging they suffer a general malaise that is detrimental to tissue function, especially in energy-hungry tissues such as muscles and the brain. The causes are still poorly understood, though a faltering of the quality control mechanism of mitophagy due to loss of mitochondrial fission appears to be involved. Increased NAD+ appears to override this decline to some degree, albeit without addressing any of the underlying and still problematic root causes.

In early human trials, NAD+ upregulation has been shown to modestly improve vascular function in older individuals, most likely by reversing some of the dysfunction in smooth muscle cell behavior. In mice a broader range of benefits has been demonstrated, though it remains to be seen how many of those also appear in humans to a significant degree. The work here is more along the same lines, in which researchers show that nicotinamide riboside supplementation can restore intestinal stem cell function in older mice. This should improve tissue function, but again it is worth bearing in mind that this is only overriding a reaction to the underlying damage of aging – it doesn’t fix that damage, which still carries on to produce all of its other downstream issues.

Researchers have long studied the link between aging and sirtuins, a class of proteins found in nearly all animals. Sirtuins, which have been shown to protect against the effects of aging, can also be stimulated by calorie restriction. In 2016 it was found that, in mice, low-calorie diets activate sirtuins in intestinal stem cells, helping the cells to proliferate. In a new study, researchers set out to investigate whether aging contributes to a decline in stem cell populations, and whether that decline could be reversed.

By comparing young (aged 3 to 5 months) and older (aged 2 years) mice, the researchers found that intestinal stem cell populations do decline with age. Furthermore, when these stem cells are removed from the mice and grown in a culture dish, they are less able to generate intestinal organoids, which mimic the structure of the intestinal lining, compared to stem cells from younger mice. The researchers also found reduced sirtuin levels in stem cells from the older mice.

Once the effects of aging were established, the researchers wanted to see if they could reverse the effects using a compound called nicotinamide riboside (NR). This compound is a precursor to NAD, a coenzyme that activates the sirtuin SIRT1. They found that after six weeks of drinking water spiked with NR, the older mice had normal levels of intestinal stem cells, and these cells were able to generate organoids as well as stem cells from younger mice could.

To determine if this stem cell boost actually has any health benefits, the researchers gave the older, NR-treated mice a compound that normally induces colitis. They found that NR protected the mice from the inflammation and tissue damage usually produced by this compound in older animals. “That has real implications for health. Just having more stem cells is all well and good, but it might not equate to anything in the real world. Knowing that the guts are actually more stress-resistant if they’re NR-supplemented is pretty interesting.”


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