How Might Nutrient Rich Diets Turn Our Gut Bacteria Against Us?

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Nutrient rich diets are harmful, even if only considering the accumulation of visceral fat tissue that results from eating more calories than are strictly necessary for sustained periods of time. Visceral fat tissue produces chronic inflammation, and that in turn accelerates progression of all of the common age-related conditions. High nutrient diets also have an effect on gut bacteria, however, and it is becoming apparent that the state of these bacterial populations has a noteworthy influence on the course of long-term health. This may be as large an effect as that of exercise, but this remains to be determined in certainty.


Together with our microbes, we form a synergist relation, which is termed holobiont or metaorganism. Disturbance of this host-microbe homeostasis can lead to dysbiosis (microbial imbalance on or inside the host) and/or disease development. It is well documented that inflammatory diseases are accompanied by changes in microbial density or microbial community composition. However, comprehensive sequencing approaches have not yet led to the identification of a key pathogen, nor to the discovery of a specific pathobiome that is responsible for the disease. On the contrary, it is becoming more and more apparent that our associated microbiota is not as specific as we thought and that, even within the same individual, microbial community composition underlies strong temporal variability.

Inflammatory diseases, such as inflammatory bowel diseases, are dramatically increasing worldwide, but an understanding of the underlying factors is lacking. We here present an ecoevolutionary perspective on the emergence of inflammatory diseases. We propose that adaptation has led to fine-tuned host-microbe interactions, which are maintained by secreted host metabolites nourishing the associated microbes.

A constant elevation of nutrients in the gut environment leads to an increased activity and changed functionality of the microbiota, thus severely disturbing host-microbe interactions and leading to dysbiosis and disease development. In the past, starvation and pathogen infections, causing diarrhea, were common incidences that reset the gut bacterial community to its “human-specific-baseline.” However, these natural clearing mechanisms have been virtually eradicated in developed countries, allowing a constant uncontrolled growth of bacteria. This leads to an increase of bacterial products that stimulate the immune system and ultimately might initiate inflammatory reactions.

Link: https://doi.org/10.1128/mBio.00355-19

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Mitochondrial DNA Damage in Age-Related Macular Degeneration

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One of the early features of age-related macular degeneration, in which the retina degenerates, causing progressive blindness, is a rising level of oxidative stress in the retinal pigment epithelium. Researchers here consider a role for mitochondrial DNA damage in the generation of this oxidative damage. Mitochondria are the power plants of the cell, descendants of ancient symbiotic bacteria that still retain a little of their original DNA. They carry out energetic chemical operations that result in a flow of oxidative molecules as a by-product. Damage to mitochondrial DNA that causes loss of proteins essential to the molecular machinery inside a mitochondrion can lead to a sizable leap in production of oxidative molecules, not just by mitochondria, but exported by the cell into the surrounding tissue.


Age-related macular degeneration (AMD) is a complex eye disease that affects millions of people worldwide and is the main reason for legal blindness and vision loss in the elderly in developed countries. Although the cause of AMD pathogenesis is not known, oxidative stress-related damage to retinal pigment epithelium (RPE) is considered an early event in AMD induction. However, the precise cause of such damage and of the induction of oxidative stress, including related oxidative effects occurring in RPE and the onset and progression of AMD, are not well understood.

Many results point to mitochondria as a source of elevated levels of reactive oxygen species (ROS) in AMD. This ROS increase can be associated with aging and effects induced by other AMD risk factors and is correlated with damage to mitochondrial DNA. Therefore, mitochondrial DNA (mtDNA) damage can be an essential element of AMD pathogenesis. This is supported by many studies that show a greater susceptibility of mtDNA than nuclear DNA to DNA-damaging agents in AMD. Therefore, the mitochondrial DNA damage reaction (mtDDR) is important in AMD prevention and in slowing down its progression as is ROS-targeting AMD therapy. However, we know far less about mtDNA than its nuclear counterparts. Further research should measure DNA damage in order to compare it in mitochondria and the nucleus, as current methods have serious disadvantages.

Link: https://doi.org/10.3390/ijms20102374

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Reviewing the Reserve Supply of Immature Neurons in the Adult Brain

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To what degree can the adult brain restructure and regenerate itself? In one sense the components of the central nervous system, brain included, are clearly among the least regenerative of tissues in mammalian species. In another sense the brain is capable of significant compensatory change following damage. Further, the normal operation of the brain over time depends upon the plasticity of neural circuits in response to changing circumstances: learning, memory, and so forth.

The authors of today’s open access research propose that these capacities for regeneration and change may arise not just from a supply of daughter cells created by neural stem cell populations, but also from a reserve population of immature neurons that are generated during early development and then retained throughout life. This hypothesis lacks solid evidence, but it is this sort of speculation – what is this apparently inactive cell population actually doing? – that drives further investigations.

Looking at the broader picture, it is a question of great interest to researchers in the field as to whether or not it is possible to upregulate the existing mechanisms of repair and plasticity in the central nervous system. Are there comparatively simple signal or regulatory proteins that can be targeted to change cell behavior in ways that provoke greater regeneration and maintenance in the aging brain? This is an open question for human medicine, though it is certainly the case that many studies in mice have provided promising data over the years. It remains to be seen as to where that work will lead.

Newly Generated and Non-Newly Generated “Immature” Neurons in the Mammalian Brain: A Possible Reservoir of Young Cells to Prevent Brain Aging and Disease?


The aging of the brain, especially in the light of a progressive increase of life expectancy, will impact the majority of people during their lifetime, putting at stake their later life and that of their relatives. This cannot be seen only as a health problem for patients but as a more general, worrisome, social, and economic burden. In spite of fast and substantial advancements in neuroscience/neurology research, resolutive therapeutic solutions are lacking.

For a long time, some hopes have been recognized in structural plasticity: The possibility for a “generally static” brain to undergo structural changes throughout life that may go beyond the modifications of synaptic contacts between pre-existing neuronal elements. During the last five decades, the discovery that the genesis of new neurons (adult neurogenesis) can still occur in some regions of the central nervous system (CNS) supported such hopes, suggesting that young, fresh neurons might replace the lost/damaged ones.

The real roles and functions of adult neurogenesis are far from being elucidated, and it appears clear that the new neurons can mainly serve physiological functions within the neural circuits, rather than being useful for repair. Interestingly, and adding further complexity, non-newly generated, immature neurons sharing the same molecular markers of the newly born cells are also present in the mature brain.

Independently from any specific physiological function (at present unknown), the novel population of “immature” neurons (nng-INs) raise interest in the general context of mammalian structural plasticity, potentially representing an endogenous reserve of “young”, plastic cells present in cortical and subcortical brain regions. Finding more about such cells, especially regarding their topographical and phylogenetic distribution, their fate with increasing age, and the external/internal stimuli that might modulate them, would open new roads for preventive and/or therapeutic approaches against age-related brain damage and cognitive decline.

A current hypothesis is that in the large-brained, long-living humans the neurons generated at young ages might mature slowly, maintaining plasticity and immaturity for very long periods. Hence, immature neurons, intended as both newly generated (in neurogenic sites) and non-newly generated (nng-INs in cortex and subcortical regions), might represent a form of “reserve” of young neurons in the absence of continuous cell division. In this context, solid evidence suggests that “adult” neurogenesis in mammals should not be considered as a constitutive, continuous process taking place at the same rate throughout life, but rather as an extension of embryonic neurogenesis, which can persist for different postnatal periods by decreasing (even ceasing) at different ages and in different brain regions.

There is no sharp boundary between developmental processes and subsequent tissue maintenance and aging processes and some events, such as adult neurogenesis, have all the hallmarks of late developmental processes. In that sense, adult neurogenesis is not at all similar to the cell renewal/regenerative processes known to occur in other stem cell systems, such as the skin, blood, or bone; rather, it is characterized by progressive neural stem cell/progenitor depletion, the cell addition being directed at the completion of organ or tissue formation, not at the replacement of lost cells. This aspect is more prominent and precocious in large-brained mammals, especially humans.

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How Sulforaphane in Broccoli May Benefit Those With Schizophrenia, Autism and Alzheimer’s

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Science has proven time after time that food is potent medicine. Broccoli, for example, has a solid scientific foundation showing it’s one of the most valuable health-promoting foods around. While it contains several health-promoting compounds, one of the most widely studied is sulforaphane.

The cancer-fighting properties of sulforaphane are perhaps the most well-known, but it has also been shown to benefit your heart and brain, boosting detoxification1 and helping prevent and/or treat high blood pressure,2 heart disease, Alzheimer’s3 and even autism.4,5,6 Now, researchers report sulforaphane may also be helpful in the treatment of schizophrenia.7,8,9

Sulforaphane May Improve Cognition in Patients With Schizophrenia

An initial study,10 published in Clinical Psychopharmacology and Neuroscience in 2015, involved just 10 outpatients with schizophrenia. Patients were given 30 milligrams (mg) of sulforaphane glucosinolate per day for eight weeks. As reported by the authors:

“Clinical symptoms using the Positive and Negative Syndrome Scale (PANSS) and cognitive function using the Japanese version of CogState battery were evaluated at the beginning of the study and at week 8.

A total of 7 patients completed the trial. The mean score in the Accuracy component of the One Card Learning Task increased significantly after the trial … This result suggests that SFN [sulforaphane] has the potential to improve cognitive function in patients with schizophrenia.”

Schizophrenia Linked to Chemical Imbalances in the Brain

More recently, a series of three animal and human studies11 by researchers at Johns Hopkins School of Medicine suggest sulforaphane may also benefit patients with schizophrenia by helping to rebalance the glutamate levels in their brain. As reported by Neuroscience News:12

“Schizophrenia is marked by hallucinations, delusions and disordered thinking, feeling, behavior, perception and speaking. Drugs used to treat schizophrenia don’t work completely for everyone, and they can cause a variety of undesirable side effects, including metabolic problems increasing cardiovascular risk, involuntary movements, restlessness, stiffness and ‘the shakes.’”

According to Dr. Akira Sawa, director of the Johns Hopkins The Schizophrenia Center, “It’s possible that future studies could show sulforaphane to be a safe supplement to give people at risk of developing schizophrenia as a way to prevent, delay or blunt the onset of symptoms.”13

One of the studies14 in this series, published January 9, 2019, in JAMA Psychiatry, assessed differences in brain metabolism between 81 schizophrenic patients and 91 healthy controls, finding schizophrenics had lower levels of key brain chemicals associated with the disease — glutamate, N-acetylaspartate,15 GABA and glutathione — in their anterior cingulate cortex, a brain region involved in executive function, emotional affect and cognition.16

According to the paper17 “Cognitive and Emotional Influences in Anterior Cingulate Cortex,” this brain region appears to be “the brain’s error detection and correction device,” and “is part of a circuit involved in a form of attention that serves to regulate both cognitive and emotional processing.”

In the brain, glutamate — an excitatory neurotransmitter18 — plays an important role in brain cell communication, and lower levels have been linked to both schizophrenia and depression.

Schizophrenics also had lower levels of N-acetylaspartate in the orbitofrontal region, an area involved in cognitive processing and decision-making, as well as the thalamus, an area involved in the relaying of sensory signals and the regulation of consciousness.

They also had lower levels of glutathione in the thalamus. Glutathione, a master antioxidant produced by your body, is made up of glutamate, cysteine and glycine, and is a physiologic reservoir of neuronal glutamate.19

Modulating Glutamate Levels May Improve Schizophrenia

For the second study in the series, the researchers focused on the management of glutamate in the brain. As reported by Neuroscience News,20 they wondered whether faulty glutamate management might be a key problem in the disease, and whether drugs could be used to “shift this balance to either release glutamate from storage when there isn’t enough, or send it into storage if there is too much.”

So, in this study,21 published February 12, 2019, in PNAS, they blocked an enzyme that turns glutamate into glutathione in the brain cells of rats, using a drug called L-Buthionine sulfoximine, thereby allowing glutamine to be used up.

“The researchers found that these nerves were more excited and fired faster, which means they were sending more messages to other brain cells. The researchers say shifting the balance this way is akin to shifting the brain cells to a pattern similar to one found in the brains of people with schizophrenia,” Neuroscience News 22 explains.

Next, to increase the level of glutamine stored as glutathione, they used sulforaphane, as it activates a gene that makes an enzyme required for the synthesis of glutathione from glutamate. As expected, this slowed the speed with which neurons fired.

In other words, it helped normalize the brain cells, allowing them to behave in a manner more like healthy controls. Dr. Thomas Sedlak, Ph.D., assistant professor of psychiatry and behavioral sciences told Neuroscience News:23

“We are thinking of glutathione as glutamate stored in a gas tank. If you have a bigger gas tank, you have more leeway on how far you can drive, but as soon as you take the gas out of the tank it’s burned up quickly. We can think of those with schizophrenia as having a smaller gas tank.”

Sulforaphane Boosts Glutathione Levels in the Brain

In an earlier pilot study24 (counted as the third in this series) by the same team, published in the May 2018 issue of Molecular Neuropsychiatry, they used mice and healthy human subjects to assess the effect of sulforaphane on glutathione levels in the brain. Here, patients with a history of psychiatric illness were specifically excluded.
As explained by the authors:

The participants completed two visits, scheduled 7 days (1 week) apart. The participants were given 100 µmol sulforaphane as standardized broccoli sprout extract in the form of 2 gel capsules, and instructed to ingest the extract each morning for 1 week …

Urine and blood specimens were collected prior to the first dose of broccoli sprout extract and within 4 h of the final dose. MRS [magnetic resonance spectroscopy] scans were performed prior to the first dose and within 4 h of ingesting the final dose …

Following 1-week administration of sulforaphane, the study participants demonstrated a significant augmentation of GSH in non-monocytes that include a mixture of T cells, B cells, and NK cells. The GSH level was 9.22 nmol/mL before sulforaphane administration and 12.2 nmol/mL following sulforaph­ane administration, a 32% increase …

We report that a short-term administration of sulfo­raphane was sufficient to significantly increase peripheral GSH levels in human subjects. We found an increase in GSH in the HP [hippocampus], but not elsewhere in the brain regions assessed. The peripheral GSH ratio had a strong and significantly positive correlation with brain GSH levels in the THAL [thalamus] upon sulforaphane treatment …

[I]n a submitted study, we will report that peripheral GSH levels may be correlated with cognitive functions. We thus posit the significance of exploring the possible correlations between peripheral GSH and clinical/neuropsychological measures and the influence of sulforaphane on such functional measures that are altered in neuropsychiatric disorders. The present study is a key first step toward such future studies.”

In summary, these findings suggest sulforaphane might be a safe alternative to help reduce psychosis and hallucinations in schizophrenic patients, although the researchers warn more studies are required to identify optimal dosing and assess long-term effects.

Study Series Suggests Sulforaphane May Improve Symptoms of Autism

Another series of studies suggests cruciferous vegetables high in sulforaphane might benefit those with autism spectrum disorder (ASD), primarily by upregulating genes that protect against oxidative stress, inflammation and DNA damage, “all of which are prominent and possibly mechanistic characteristics of ASD,” the authors say.25

Sulforaphane also boosts antioxidant capacity, glutathione synthesis, mitochondrial function, oxidative phosphorylation and lipid peroxidation, while lowering neuroinflammmation. According to the researchers, these characteristics also make it suitable for the treatment of ASD.26

The first study,27 published in 2014, found daily treatment with dietary sulforaphane significantly reduced the severity of “socially impaired behavior” in children with ASD after 18 weeks. Improvements became obvious (compared to those in the placebo group) at four weeks of treatment.

At 18 weeks, the sulforaphane treatment group had a 34% reduction in Abberant Behavior Checklist (ABC) scores and a 17% reduction in Social Responsiveness Scale (SRS) scores. According to the authors:28

“[A] significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication. Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels.”

Case Series Highlights Success Stories With Sulforaphane Treatment

The second study,29 published in 2017, presented a case series follow-up of patients who continued the sulforaphane treatment after the first study ended. Here’s a limited outtake from the narrative provided by one of the families whose son is referred to as “R”:

“R’s parents wanted to help him: ‘He would make constant noises and did all these abnormal motor tics; [we] felt like he really had no control [over his behavior and body] and it was just noise, not functional words. He didn’t have any expressive language.’

R’s parents saw several medical specialists who prescribed a total of 18 different medications, all of which had either minimal or negative effects on R. ‘Nothing changed the constant noises or the terrible rage attacks,’ until R took SF [sulforaphane] …

R’s family took him to the Lurie Center at Massachusetts General Hospital where we were conducting the study on the effects of SF on males with ASD. The study was a randomized double-blind placebo-controlled trial. However, within days, R’s mother believed that he was taking SF:

‘I knew that he was on the study drug because I saw such a change so quickly. I want to scream from the rooftops and tell people to give the kids broccoli sprouts [extract] because literally, it changed my life,’ reported R’s mother.

‘Now we can go to the movies, restaurants, plays, we went on vacation with another family, we go to church, we just went to a concert, things we could never do before are now possible. [I am] able to have confidence and he [R] is more confident as well.’

N.B. Such a rapid response was unusual in the context of what was observed by the study physicians with other subjects. When responses to supplementation were observed, they generally took 3 or 4 weeks to become manifest. In this case, the study team actually wondered whether the mother might be exhibiting a placebo response; however, the ABC subscales and both ABC and SRS overall scores for R did also change.”

New Mechanism of Action Revealed

The third paper30 in this series, a trial progress report published in 2018, assessed the safety, clinical effects and mechanisms of action of sulforaphane in ASD. Interestingly, this paper describes how sulforaphane mimics “the fever effect” in ASD. This is where high fever temporarily improves behavior in autistic children. The researchers explain:

“Fever stimulates heat shock proteins (HSP) and cellular stress responses, leading to improved synaptic function and long-range connectivity. Expression of gene transcription by NFE2L2 (Nrf2), which is reduced in ASD, also increases during fever.

Sulforaphane (SF), an isothiocyanate obtained from broccoli sprouts, induces HSP and Nrf2 as well as ‘cell-protective’ responses that may benefit ASD through common cellular mechanisms underlying heterogeneous phenotypes.”

While this trial was still incomplete at publication, as only 46 participants out of a planned 50 had been enrolled, preliminary analysis showed “26% participants were much/very much improved at seven weeks, 38% at 15 weeks, 64% at 22 weeks, and 64% at 30 weeks,” the researchers said, adding that “preliminary results show that sulforaphane appears to be safe and effective in children with ASD.”

Sulforaphane Stands Out as Potential Alzheimer’s Treatment

Sulforaphane may also be useful in the treatment of Alzheimer’s disease. In a 2018 study,31 mice with Alzheimer’s were treated with sulforaphane for four months, which significantly inhibited both the generation and accumulation of amyloid-beta, and alleviated several pathological changes associated with Alzheimer’s, including oxidative stress and neuroinflammation.

The mice also demonstrated cognitive benefits, remaining normal, cognitively speaking, compared to wild-type mice at 10 months of age, which is when dementia typically begins in Alzheimer’s mice. In tests of neurons themselves, pretreating cortical neurons with sulforaphane protected them against injury caused by amyloid beta.

An earlier study32 published in 2009 revealed that antioxidants — including sulforaphane — protect cells from oxidative damage, facilitate removal of the amyloid-beta peptide and reduce abnormal protein-related causes of disease.

In studying how sulforaphane interacts with amyloid-beta to prevent various neurodegenerative processes, researchers of a 2014 study33 used liquid chromatography/electrospray ionization mass spectrometry to reveal that amyloid-beta is less likely to aggregate in the presence of sulforaphane.

Another 2014 study34 showed that, in mice with Alzheimer’s-like lesions (induced in part by administration of aluminum), sulforaphane reduced neurobehavioral deficits by promoting the growth of new neurons (neurogenesis) as well as reducing the aluminum load.

Broccoli Provides Many Health Benefits

While this article focuses on the neurological benefits of broccoli, research has revealed a long list of health benefits associated with this cruciferous vegetable, including a reduced risk for:35

Osteoarthritis36

Cancer — Studies have shown sulforaphane supports normal cell function and division while causing apoptosis (programmed cell death) in colon,37 prostate,38 breast39 and tobacco-induced lung cancer40 cells, and reducing the number of cancerous liver tumors in mice41

High blood pressure42

Heart disease43

Kidney disease44

Insulin resistance45 and Type 2 diabetes46

Obesity47

Allergies48,49

Broccoli and other water- and nutrient-rich veggies also support healthy liver function, which in turn promotes optimal functioning of your natural detoxification systems. Broccoli sprouts, in particular, have been shown to help detox environmental pollutants such as benzene.50,51

This is important for virtually everyone these days, but especially women of childbearing age. Autistic children are known to have higher levels of environmental toxins in their system, and this underlying toxic burden plays a significant role.

Healthy liver function also helps promote healthy, beautiful skin, making broccoli a good antiaging food. What’s more, the sulforaphane in broccoli also helps repair skin damage.

How to Boost Sulforaphane Benefits of Broccoli

To boost the benefits of sulforaphane in broccoli and other cruciferous veggies, pair them with a myrosinase-containing food.52 Myrosinase is an enzyme that converts the precursor gluocosinalate, glucoraphanin, to sulforaphane. Examples include mustard seed,53 daikon radishes, wasabi, arugula or coleslaw, with mustard seed being the most potent.

Adding a myrosinase-rich food is particularly important if you eat the broccoli raw, or use frozen broccoli. Ideally, broccoli should be steamed for three to four minutes to increase the available sulforaphane content. This light steaming eliminates epithiospecifier protein — a heat-sensitive sulfur-grabbing protein that inactivates sulforaphane — while retaining the myrosinase in the broccoli.54

Steaming is important, because without myrosinase, your body cannot absorb sulforaphane. If you opt for boiling, blanch the broccoli in boiling water for no more than 20 to 30 seconds, then immerse it in cold water to stop the cooking process.

If you prefer raw food, you’d be better off eating raw broccoli sprouts instead of mature broccoli. According to Dr. Paul Talalay, professor of pharmacology and co-author of the 1997 study55 “Broccoli Sprouts: An Exceptionally Rich Source of Inducers of Enzymes That Protect Against Chemical Carcinogens,” “Three-day-old broccoli sprouts consistently contain 20 to 50 times the amount of chemoprotective compounds found in mature broccoli heads.”56 As a result, you can eat far less of them while still maximizing your benefits.

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The Pension Industry Will Change Radically, Willingly or Otherwise

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Promises to pay at a future date are a dangerous tool in the hands of politicians and state employees, those who suffer little to no personal consequences when past promises are revealed to be based on faulty assumptions and thin air. Either someone ends up paying, usually the taxpayers, or the promises are broken. Pensions are, of course, just such a promise. The pensions industry in the US is a good example of the way in which entitlement schemes run awry even without any sort of external shock to the system, such as large numbers of pension recipients suddenly living 5-10 years longer than the models predict. This seems likely to happen in the relatively near future, given progress towards the effective targeting of mechanisms of aging by the research and medical development communities. There must and will be radical change in pensions, either willingly or otherwise.


If you work in social security, it’s possible that your nightmares are full of undying elderly people who keep knocking on your door for pensions that you have no way of paying out. Tossing and turning in your bed, you beg for mercy, explaining that there’s just too many old people who need pensions and not enough young people who could cover for it with their contributions; the money’s just not there to sustain a social security system that, when it was conceived in the mid-1930s, didn’t expect that many people would ever make it into their 80s and 90s.

When you wake up, you’re relieved to realize that there can’t be any such thing as people who have ever-worsening degenerative diseases yet never die from them, but that doesn’t make your problem all that better; you still have quite a few old people, living longer than the pension system had anticipated, to pay pensions to, and the bad news is that in as little as about 30 years, the number of 65+ people worldwide will skyrocket to around 2.1 billion, growing faster than all younger groups put together. Where in the world is your institution going to find the budget?

Suppose for a moment that human aging never existed and that, barring accidents and communicable diseases, people went on living for centuries – their health, independence, and most importantly, ability to work, remaining pretty much constant over time. In a scenario like this, it’s difficult to imagine why any government would go through the trouble of setting up a pension system that works the way the current one does. Paying out money to perfectly able-bodied people to do nothing for the rest of their lives just because they’re over 65 would make no sense at all.

Thus retirement exists out of necessity more than desire. The health of average retirees doesn’t interfere just with their ability to work but also to enjoy life in general. Most people over the age of 65 suffer two or more chronic illnesses; the risk of developing diabetes, cancer, cardiovascular diseases, dementia, and so on skyrockets with age. Many people imagine a longer, drawn-out old age in which ill health and the consequent medical expenses and pensions are extended accordingly, just as in the nightmares of social security planners. This is most definitely not what life extension is about, and it’s obvious that extending old age as it is right now would not be a solution to the problem of pensions.

However, lifespan and healthspan – that is, the length of your life and the portion of life you spend in good health – are causally connected; you don’t just drop dead because you’re 80 or 90 irrespective of how healthy you are. The reason we tend to die at around those ages is that our bodies accumulate different kinds of damage in a stochastic fashion; as time goes by, the odds of developing diseases or conditions that eventually become fatal go higher and higher, even though which specific condition will kill you depends a lot on your genetics, lifestyle, and personal history. The idea behind life extension isn’t to just “stretch” lifespan; rather, the idea is to extend healthspan, that is preserving young-adult-like good health well into your 80s or 90s, and the logical consequence of being perfectly healthy for longer is that you will also live for longer.

Again, the fundamental reason that pensions exist is to economically support people who are no longer able to do it themselves. We need to have such a system in place if we don’t want to abandon older people to their fate. If life extension treatments take ill health and age-related disabilities out of the equation entirely, pensions as we know them today will no longer be needed, because you will be able to support yourself through your own work regardless of your age.

Link: https://www.leafscience.org/the-future-of-pensions/

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Walking Pace Correlates with Life Expectancy

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Walking pace, like grip strength, is one of the simple measures used by physicians to assess the progression of frailty in old age. Researchers here report on epidemiological data that shows an association between life expectancy and walking pace, in that older individuals who walk more slowly tend to have a shorter life expectancy. This is only to be expected: a slower pace tends to arise due to the presence of chronic age-related disease, lack of fitness, and in general a higher burden of cell and tissue damage, all of which are known to lead to a greater mortality risk.


People who report that they have a slower walking pace have a lower life expectancy than fast walkers. The research, using data from the UK Biobank of 474,919 people recruited within the UK, found those with a habitually fast walking pace have a long life expectancy across all levels of weight status – from underweight to morbidly obese. Underweight individuals with a slow walking pace had the lowest life expectancy (an average of 64.8 years for men, 72.4 years for women). The same pattern of results was found for waist circumference measurements. This is the first time research has associated fast walking pace with a longer life expectancy regardless of a person’s body weight or obesity status.

“Our findings could help clarify the relative importance of physical fitness compared to body weight on life expectancy of individuals. In other words, the findings suggest that perhaps physical fitness is a better indicator of life expectancy than body mass index (BMI), and that encouraging the population to engage in brisk walking may add years to their lives. Studies published so far have mainly shown the impact of body weight and physical fitness on mortality in terms of relative risk, for example a 20 per cent relative increase of risk of death for every 5 unit BMI increase, compared to a reference value of a BMI of 25 (the threshold between normal weight and overweight). However, it is not always easy to interpret a “relative risk”. Reporting in terms of life expectancy, conversely, is easier to interpret and gives a better idea of the separate and joint importance of body mass index and physical fitness.”

Link: https://www.leicestershospitals.nhs.uk/aboutus/our-news/press-release-centre/?entryid8=67262

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Cofilin May Link Amyloid-β Aggregation and Tau Aggregation in Alzheimer's Disease

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The early stage of Alzheimer’s disease is characterized by the slowly increasing aggregation of amyloid-β into solid deposits, something that may occur due to failing clearance of metabolic waste from the brain via drainage paths for cerebrospinal fluid. The complex biochemistry surrounding amyloid-β is damaging to the operation of brain cells, but not damaging enough to cause more than mild cognitive impairment in and of itself. Unfortunately, the presence of amyloid-β also in some way creates the foundation for the second stage of the condition, in which a modified form of tau protein forms aggregates known as neurofibrillary tangles. These aggregates and their surrounding biochemistry are far more harmful, causing major neural dysfunction and cell death in the ultimately fatal end stages of Alzheimer’s disease.

How does amyloid-β aggregation cause tau aggregation? The answer is unlikely to be simple, and unlikely to involve only one mechanism, as little in biochemistry is anything other than complicated. There is a good deal of evidence to suggest that chronic inflammation and associated dysfunction of immune cells such as microglia in the central nervous system are important bridging mechanisms between amyloid-β and tau. For example, clearing out senescent microglia and thus reducing neuroinflammation turns back tau aggregation in mouse models. Given present progress in senolytic therapies, it won’t be too long now before the research community finds out how well this approach does in humans.

What about other mechanisms, however? Today’s research suggests that amyloid-β disrupts the normal activity of tau in a previously unsuspected way. Tau is a normally a part of the cellular cytoskeleton, the microtubules that support cell structure. The presence of amyloid-β encourages another protein, cofilin, to disrupt the microtubules and thus free up tau from its usual location and behavior. The evidence from mice in this study supports the view that this process is important in the generation of the altered forms of tau that eventually form neurofibrillary tangles. How does this process interact with neuroinflammation and bad behavior on the part of microglia? That remains to be determined.

Cofilin may be early culprit in tauopathy process leading to brain cell death


The two primary hallmarks of Alzheimer’s disease are clumps of sticky amyloid-beta (Aβ) protein fragments known as amyloid plaques and neurofibrillary tangles of a protein called tau. Abnormal accumulations of both proteins are needed to drive the death of brain cells, or neurons. But scientists still have a lot to learn about how amyloid impacts tau to promote widespread neurotoxicity, which destroys cognitive abilities like thinking, remembering and reasoning in patients with Alzheimer’s. While investigating the molecular relationship between amyloid and tau, neuroscientists have now discovered that the Aβ-activated enzyme cofilin plays an essential intermediary role in worsening tau pathology.

The research introduces a new twist on the traditional view that phosphorylation of tau is the most important early event in tau’s detachment from brain cell-supporting microtubules and its subsequent build-up into neurofibrillary tangles. These toxic tau tangles disrupt brain cells’ ability to communicate, eventually killing them. Without microtubules, axons and dendrites could not assemble and maintain the elaborate, rapidly changing shapes needed for neural network communication, or signaling. Tau molecules are like the railroad track ties that stabilize and hold train rails (microtubules) in place.

Using a mouse model for early-stage tauopathy, researchers showed that Aβ-activated cofilin promotes tauopathy by displacing the tau molecules directly binding to microtubules, destabilizes microtubule dynamics, and disrupts synaptic function – all key factors in Alzheimer’s disease progression. Unactivated cofilin did not. The researchers also demonstrated that genetically reducing cofilin helped prevent the tau aggregation leading to Alzheimer’s-like brain damage in mice. “Our data suggests that cofilin kicks tau off the microtubules, a process that possibly begins even before tau phosphorylation. That’s a bit of a reconfiguration of the canonical model of how the pathway leading to tauopathy works.”

Activated cofilin exacerbates tau pathology by impairing tau-mediated microtubule dynamics


Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. While the accumulation of Aβ is pivotal to the etiology of AD, both the microtubule-associated protein tau (MAPT) and the F-actin severing protein cofilin are necessary for the deleterious effects of Aβ. However, the molecular link between tau and cofilin remains unclear. In this study, we found that cofilin competes with tau for direct microtubule binding in vitro, in cells, and in vivo, which inhibits tau-induced microtubule assembly. Genetic reduction of cofilin mitigates tauopathy and synaptic defects in Tau-P301S mice and movement deficits in tau transgenic C. elegans. The pathogenic effects of cofilin are selectively mediated by activated cofilin, as active but not inactive cofilin selectively interacts with tubulin, destabilizes microtubules, and promotes tauopathy. These results therefore indicate that activated cofilin plays an essential intermediary role in neurotoxic signaling that promotes tauopathy.

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Journalists Have Very Fragmentary, Incomplete Views of the Longevity Industry

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The lengthy and somewhat overwrought article I’ll point out today is a good example of the way in which journalists fail when writing on the topic of the growing biotechnology industry that is making the first steps towards the medical control of aging. They talk to just a few people, and thus have a very narrow (generously) or absolutely incorrect (more accurately) view of what might be happening, the prospects for the future, and the shape of the field as a whole. In this case the few people are the folk at AgeLab at MIT, and George Church, with a focus on the veterinary deployment of gene therapies by Rejuvenate Bio, and a fairly traditional Alzheimer’s researcher.

To speak directly, and without meaning to be cruel about it, AgeLab should not exist. It is an entity focused on coping with the realities of aging, making recommendations on small ways that older people might do a little better under the burden of aging. This is a waste of funding in a world in which there is even the slightest possibility of treating aging as a medical condition, and the present state of senolytics, among many other signs, shows that there is far more than a slight possibility of that outcome. Unfortunately AgeLab is far from the only organization set up on the premise that aging cannot be changed, and that the only thing to be done is cope. Holding it up in any discussion of where things might be going in the future is just silly. As rejuvenation works, the AgeLabs of the world will vanish, and rightfully so.

The genetic approach to aging, of using gene therapies of various sorts to adjust the operation of metabolism in late life is espoused by George Church and others. This seems to me just an incremental advance over small molecule calorie restriction mimetic or other stress response upregulation efforts. Gene therapy can be more precise, with fewer off-target effects, and a more flexible, direct development program. But at the end of the day this is still largely a case of altering metabolism to better resist aging rather than addressing the underlying causes of aging. This tweaking of metabolic processes simply cannot produce sizable benefits, as the underlying damage still exists, and the gene therapy can only tweak one set of mechanisms related to that damage, leaving all the others to fester. It will certainly look at lot better than the medicines of yesterday, which failed to even achieve this much, but why aim low? This type of approach to aging is the majority of the field still, but it is not the future of therapies for aging. The effect sizes won’t be large enough and reliable enough in comparison to those of clearing senescent cells or other forms of damage repair.

The traditional Alzheimer’s researchers, those associated with a few decades of failure to make progress towards therapies, can be pessimistic. If one talks to them, but not to the researchers running new ventures and new programs that offer real signs of progress in different approaches to treating the condition, then one comes away with the idea that everything is intractable and the field is making only slow progress, if it progresses at all. Similarly, in the bigger picture, one cannot look at the longevity industry, ignore the approach of rejuvenation through repair of damage, and come away with anything other than an incomplete view of what is taking place, an incorrect view of what is important for the future, and an incorrect view of what the plausible pace of progress might be in the years ahead.

Can We Live Longer but Stay Younger?


Where fifty years ago it was taken for granted that the problem of age was a problem of the inevitable running down of everything, entropy working its worst, now many researchers are inclined to think that the problem is “epigenetic“: it’s a problem in reading the information – the genetic code – in the cells. To use a metaphor of the Harvard geneticist David Sinclair, the information in each cell is digital and perfectly stored; it’s the “readout,” the active expression of the information, that’s effectively analogue, and subject to occlusion by the equivalent of dirt and scratches on the plastic surface of a CD. Clear those off, he says, and the younger you, still intact in the information layer, jumps out – just as the younger Beatles jump out from a restored and remastered CD.

We don’t have to micromanage the repair, the Harvard molecular biologist George Church observes: “If we think epigenetically, we can see that we can make the cells industriously do the repair themselves.” He is among a group of engineer-entrepreneurs who are trying not to make better products for aging people but to make fewer aging people to sell products to. Perhaps aging is not a condition to be managed but a mistake to be fixed. Sinclair, for one, has successfully extended the life of yeast, and says that he is moving on to human trials. He is an evangelist for the advantages of what he calls “hormesis” – the practice of inducing metabolic stress by short intense exercise or intermittent fasting. “Every day, try to be hungry and out of breath” is his neatly epigenetic epigram.

Anti-aging research, in its “translational,” or applied, form, seems to be proceeding along two main fronts: through “small molecules,” meaning mostly dietary supplements that are intended to rev up the right proteins; and, perhaps more dramatically, through genetic engineering. Typically, genetic engineering involves adding or otherwise manipulating genes in a population of animals, often mice, perhaps by rejiggering a mouse’s genome in embryo and then using it to breed a genetically altered strain. In mice studies, genetic modifications that cause the rodents to make greater amounts of a single protein, sirtuin 6, have resulted in longer life spans (although some scientists think that the intervention merely helped male mice to live as long as female mice).

Church and Noah Davidsohn, a former postdoc in his lab, have engaged in a secretive but much talked-about venture to make old dogs new. They have conducted gene therapy on beagles with the Tufts veterinary school, and are currently advertising for Cavalier King Charles spaniels, which are highly prone to an incurable age-related heart condition, mitral-valve disease; almost all of them develop it by the age of ten. Using a genetically modified virus, Church and Davidsohn’s team will insert a piece of DNA into a dog’s liver cells and get them to produce a protein meant to stop the heart disease from progressing. But the team has larger ambitions. It has been identifying other targets for gene-based interventions, studying a database of aging-related genes: genes that are overexpressed or underexpressed – that make too much or too little of a particular protein – as we grow old. In the CD replay of life, these are the notes that get muffled or amplified, and Davidsohn and Church want to restore them to their proper volume.

Many problems cling to this work, not least that there are surprisingly few “biomarkers” of increased longevity. One researcher makes a comparison with cancer research: we know a patient’s cancer has been successfully treated when the cancer cells go away, but how do you know if you’ve made people live longer except by waiting decades and seeing when they die? Ideally, we’d find something that could be measured in a blood test, say, and was reliably correlated with someone’s life span.

Church is optimistic about the genetic-engineering approach. “We know it can work because we’ve already had success reprogramming embryonic stem cells: you can take a really old cell and turn that back into a young cell. We’re doing it now. Most of the work was done in mice, where we’ve extended the life of mice by a factor of two. It isn’t seen as impressive, because it’s mice, but now we’re working on dogs. There are about nine different pathways that we’ve identified for cell rejuvenation, one of which eliminates senescent cells” – moldering cells that have stopped dividing and tend to spark inflammation, serving as a perpetual irritant to their neighbors.

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Repeated Cycles of Incomplete Healing as a Cause of Aging

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The authors of the open access paper here have an intriguing view of the way in which regenerative processes run awry with age, and thus contribute to the aging process. As is the case for many single mechanism proposals regarding aging, I think that the viewpoint is useful, but the mechanism in question is probably not as important to aging as proposed here – it is one of many issues. Nonetheless, this is an interesting example of the way in which it is hard to pin down the ordering of specific mechanisms in aging; it is quite possible to argue for A to cause B or B to cause A and present a good case for either. Here, for example, dysregulated regeneration is thought to be a cause of senescent cell accumulation, whereas it is equally possible to argue that the chronic inflammatory signaling produced by senescent cells disrupts the usual short-lived cycle of inflammation that is necessary to coordinate various cell populations necessary to the regenerative process.


The rate of biological aging varies cyclically and episodically in response to changing environmental conditions and the developmentally-controlled biological systems that sense and respond to those changes. Mitochondria and metabolism are fundamental regulators, and the cell is the fundamental unit of aging. However, aging occurs at all anatomical levels. At levels above the cell, aging in different tissues is qualitatively, quantitatively, and chronologically distinct. For example, the heart can age faster and differently than the kidney and vice versa. Two multicellular features of aging that are universal are: (1) a decrease in physiologic reserve capacity, and (2) a decline in the functional communication between cells and organ systems, leading to death.

Decreases in reserve capacity and communication impose kinetic limits on the rate of healing after new injuries, resulting in dyssynchronous and incomplete healing. Exercise mitigates against these losses, but recovery times continue to increase with age. Reinjury before complete healing results in the stacking of incomplete cycles of healing. Developmentally delayed and arrested cells accumulate in the three stages of the cell danger response (CDR1, 2, and 3) that make up the healing cycle. Cells stuck in the CDR create physical and metabolic separation – buffer zones of reduced communication – between previously adjoining, synergistic, and metabolically interdependent cells. Mis-repairs and senescent cells accumulate, and repeated iterations of incomplete cycles of healing lead to progressively dysfunctional cellular mosaics in aging tissues.

Metabolic cross-talk between mitochondria and the nucleus, and between neighboring and distant cells via signaling molecules called metabokines regulates the completeness of healing. Purinergic signaling and sphingolipids play key roles in this process. When viewed against the backdrop of the molecular features of the healing cycle, the incomplete healing model provides a new framework for understanding the hallmarks of aging and generates a number of testable hypotheses for new treatments.

Link: https://doi.org/10.3390/biology8020027

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A Conservative View of the Present State of Senolytic Development for Rejuvenation

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Here, one of the leading researchers working on the biochemistry of senescent cells – and their relevance to aging – considers the state of development of senolytic therapies. These are treatments, largely small molecule drugs at this stage, but also including suicide gene therapies, immunotherapies, and more, that are capable of selectively destroying some fraction of the senescent cells present in old tissues. There is tremendous enthusiasm in the scientific and development communities for the potential to create significant degrees of rejuvenation via this approach. The results in mice are far and away more impressive and reliable than anything else that has yet been tried in the matter of aging and age-related disease. Simple one time treatments with senolytics lead to significant extension of life span and reversal of aspects of age-related disease. Leading researchers, of course, have to be far more muted when writing for scientific journals, so the tone here is more cautious than enthused.


Healthy aging is limited by a lack of natural selection, which favors genetic programs that confer fitness early in life to maximize reproductive output. There is no selection for whether these alterations have detrimental effects later in life. One such program is cellular senescence, whereby cells become unable to divide. Cellular senescence enhances reproductive success by blocking cancer cell proliferation, but it decreases the health of the old by littering tissues with dysfunctional senescent cells (SNCs). In mice, the selective elimination of SNCs (senolysis) extends median life span and prevents or attenuates age-associated diseases. This has inspired the development of targeted senolytic drugs to eliminate the SNCs that drive age-associated disease in humans.

SNCs produce a bioactive “secretome,” referred to as the senescence-associated secretory phenotype (SASP). This can disrupt normal tissue architecture and function through diverse mechanisms, including recruitment of inflammatory immune cells, remodeling of the extracellular matrix, induction of fibrosis, and inhibition of stem cell function. Paradoxically, although cellular senescence has evolved as a tumor protective program, the SASP can include factors that stimulate neoplastic cell growth, tumor angiogenesis, and metastasis, thereby promoting the development of late-life cancers. Indeed, elimination of SNCs with aging attenuates tumor formation in mice, raising the possibility that senolysis might be an effective strategy to treat cancer.

Given that our knowledge of SNCs in vivo is limited, how should researchers identify senolytic drug targets? One strategy is to identify vulnerabilities shared by cancer cells and SNCs and then use tailored variants of anticancer agents to target such vulnerabilities to selectively eliminate SNCs. Although cancer therapeutics that interfere with cell division are unsuitable as senolytic drugs, agents that block the pathways that cancer cells rely on for survival might be worth pursuing as senolytics. For example, resistance to apoptosis (a form of programmed cell death) is a feature shared by cancer cells and SNCs. Proof-of-principle evidence for the effectiveness of this strategy comes from targeting the BCL-2 protein family members: BCL-2, BCL-XL, and BCL-W. These antiapoptotic proteins are frequently overexpressed in both cancer cells and SNCs. Two targeted cancer therapeutic agents, ABT-263 and ABT-737, have been shown to selectively eliminate SNCs in mice by blocking the interactions of BCL-2, BCL-XL, and BCL-W.

Senolytic drugs that inhibit targets originally discovered in oncology could yield promising first-generation drugs to treat humans. However, this strategy may not accomplish the long-term goal of developing ideal senolytics that selectively, safely, and effectively eliminate SNCs upon systemic administration. Efforts to identify such “next-generation” senolytics could nonetheless benefit from general principles that have been used in anticancer drug discovery. For instance, it will be important to focus drug development on age-associated degenerative diseases in which SNCs are clear drivers of pathophysiology and in which senolysis could be disease modifying (e.g., osteoarthritis and atherosclerosis).

As knowledge of the fundamental biology and vulnerabilities of SNCs expands, the rational design of targeted senolytics is expected to yield therapies to eliminate SNCs that drive degeneration and disease. This positive outlook is based on successes in oncology and because the main limitation of cancer therapies – the clonal expansion of drug-resistant cells – does not apply to SNCs. Additional confidence comes from the recent progress in bringing senolytic agents into clinical trials. The first clinical trial is testing UBX0101 for the treatment of osteoarthritis of the knee. Success in these first clinical studies is the next critical milestone on the road to the development of treatments that can extend healthy longevity in people.

Link: https://doi.org/10.1126/science.aaw1299

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