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Longevity Industry Consulting Services
Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/
- Ronjon Nag on Investment in the Longevity Industry
- Reviving Cardiomyocytes via Coincubation with Mitochondria
- Outlining Some of the Science Behind Partial Reprogramming at Turn.bio
- A Short Commentary by Reason from the Giant Health Conference in 2019
- Macrophages as Both Friends and Foes in Age-Related Diseases
- On the Prospects for Intermittent Late-Life Use of Rapamycin
- Trajectories of Exercise and Mortality in Late Life
- Abnormal Stress Granules in Aging and Age-Related Disease
- Protein Acetyltransferases Influence Longevity in Short-Lived Laboratory Species
- Is There a Causative Role for Infectious Organisms in Alzheimer’s Disease?
- Loss of Mitochondrial Function with Age in Monocytes may Contribute to the Development of Atherosclerosis
- Natural Killer Cells May Act to Reduce Neuroinflammation
- The Gut Microbiome as a Contributing Factor in Alzheimer’s Disease
- Age and Dietary Fat Result in Larger Inflammatory Populations of Gut Microbes
- Arguing for More Computational Modeling to Aid the Transition to Clinical Trials that Target Aging
Ronjon Nag on Investment in the Longevity Industry
Ronjon Nag is a noted angel investor in the Bay Area, and one of the newer entries to the select community of investors interested in the longevity industry. He brings his own perspective to the table; new points of view are always welcome as the community grows in size, and as more narrowly focused specialists begin to emerge. That said, given the enormous venture funding still in waiting, looking for places to invest, there is always the perverse incentive for fund managers to consider the space of aging and longevity in the broadest sense possible. There is a pressure to invest now, invest soon, find more deals to participate in. This leads one to invest in what might be financially successful ventures, but ventures that do nothing to help address aging, and are only engaged in some form of compensation for aging. Eldercare, supportive services, tools to help people who have lost function. I expect many funding institutions to lose their way in this fashion.
These are, of course, interesting times for investors, to say the least: we are amidst something of a hysteria regarding all things viral, and also in the opening weeks of a bear market that is long overdue and thus likely to be more unpleasant than usual. If one had to invest somewhere under the present circumstances, there are certainly worse options than a preclinical biotech company working on new therapies, however. Such a company is essentially immune to the vagaries of the broader market at any time other than when it has to raise funds. For much of its life, it keeps to itself, carries out its research, and engages with regulators rather than customers. The opening weeks of a crash are a great time to provide the funds for a biotech company to carry out a year or two of work. By the time the company is ready for the next step and the next round of fundraising, the market will have turned around.
Talking Longevity investment and risk with Ronjon Nag
We understand that you’re looking at longevity as a dedicated investment category – what are the main differences you see to regular healthcare investing?
We look at longevity in the widest sense. In addition to biotech there could be investments in areas such as lifelong learning, fintech for the aged, and work opportunity platforms for the aging workforce. Cutting across these themes, we like to see a computational element and the application of artificial intelligence and data-mining within these companies. I tend to agree that this is a new space that will develop as a pure play over the next few years – both in terms of understanding the landscape and having enough quality targets to invest in. I look at artificial intelligence, longevity, and healthcare and cover all those segments to have enough vehicles to invest in.
You’ve helped over 50 companies secure funding – what are you looking for in new start-ups?
Firstly, we typically like to invest very early, at the seed or pre-stage stage, often being among the first to write checks for new startups; so early stage is one dimension. We like to help shape the company at the earliest stages. Secondly, we like to invest in difficult technologies, which usually means they are unique and have very little competition. As such patents, although helpful, are not what we particularly look for – we would rather we see the potential for a business-technology ‘moat’ combination irrespective of any patent position. Thirdly, the product, technology and team must have strong science and/or computational components. An ideal team would be recent doctoral graduates combined with seasoned industrialists who get along with each other.
We cover longevity in a wide context – i.e. beyond rejuvenation technologies, what areas do you categorise as longevity?
Yes, we have the same view; there will be many societal impacts and there will be many different products other than biotech. These could be robots (helpers or companions), self-driving vehicles, workplace marketplaces, or telecommunications enhancers to allow for at home-work interactivity. For example when developing products for the disabled the products then will be used by a wider audience. Previously texting as a communication method allowed mobile phone makers to enable communication with deaf people, yet it turned out that this functionality was liked and widely used by everybody.
Are there any longevity companies that you’ve invested in that would be of interest to our readers?
There is a macro trend of increasing computation capability, both in terms of computer processing speed and increased availability of medical data. Healx.ai is trying to speed up the production of drugs by a factor of 20, and also reduce the cost of drug discovery by a factor of 20. The initial targets are diseases, but one would expect that hundreds of treatments could be created at a fraction of a cost of traditional methodologies. Another one is Exonate which has a treatment for macular degeneration – the normal treatment requires an injection into the eye which is not very pleasant for the patient or the doctor. Exonate is working on an eye drop and has a strategic arrangement with Janssen.
Reviving Cardiomyocytes via Coincubation with Mitochondria
It has been known for a number of years that cells can ingest mitochondria and put them to work. Researchers here demonstrate that mitochondrial function in heart muscle cells can be improved by co-culturing them with free mitochondria harvested from other cells. The hope is that cells produced for transplantation into heart disease patients can be made more vigorous and effective via this means. Further, it is perhaps the case that mitochondria can be delivered in large numbers into the aging heart in order to improve the function of that tissue in situ.
Mitochondria are the power plants of the cell, each cell containing hundreds of these bacteria-like organelles that are essential to cell function. They produce the chemical energy store molecule adenosine triphosphate, used to power cellular processes. Unfortunately, mitochondrial activity declines with age for reasons that appear related to alterations in the mitochondrial dynamics of fusion and fission, and a related failure of the quality control mechanism of mitophagy, which normally acts to recycle worn and damage mitochondria. Cells become overtaken by large mitochondria as a result of too little fission, resistant to mitophagy.
Efforts to restore mitochondrial function remain at a comparatively early stage. The only practical methodologies presently available, such as NAD+ upregulation and mitochondrially targeted antioxidants, do appear to restore mitophagy and mitochondrial function in older tissues to some degree, but the effect sizes are neither large nor reliable, judging from human trials carried out to date. Better therapies are needed, and one possible approach to this challenge is the periodic delivery of new mitochondria. It remains to be seen how long fresh mitochondria will last before succumbing to the same environmental factors that degraded native mitochondria, but initial results here suggest that the benefit is short-lived, on the order of a few days to a week.
Researchers demonstrate the ability to supercharge cells with mitochondrial transplantation
Researchers have shown that they can give cells a short-term boost of energy through mitochondrial transplantation. Researchers first isolated mitochondria by differential centrifugation, followed by transplantation through coincubation. Once the mitochondria had settled in their new host cells, they performed metabolic flux analysis to measure two key parameters: the oxygen consumption rate and the extracellular acidification rate, which provide important information about cellular metabolism and how well the cells are consuming/producing energy. The analyses were conducted at two, seven, 14 and 28 days.
“Regarding the viability of mitochondrial transplantation in different cell lines, we’ve done a lot of variations, including work with skeletal muscle cells, T-cells, and cardiomyocytes. We even tested the feasibility of transplanting mitochondria from rat cells to commercially available human cells, in our lab, to see if there’s a mechanism that prevents such a procedure; we found that transplanting mitochondria between different species is also possible.” Next, the team plans to investigate whether the internalized mitochondria establish signaling with the cell’s nucleus and whether they’ll be adopted by the host on a long-term basis.
Bioenergetics Consequences of Mitochondrial Transplantation in Cardiomyocytes
We first established the feasibility of autologous, non-autologous, and interspecies mitochondrial transplantation. Then we quantitated the bioenergetics consequences of non-autologous mitochondrial transplantation into cardiomyocytes up to 28 days. Compared with the control, we observed a statistically significant improvement in basal respiration and ATP production 2-day post-transplantation, accompanied by an increase in maximal respiration and spare respiratory capacity, although not statistically significantly. However, these initial improvements were short-lived and the bioenergetics advantages return to the baseline level in subsequent time points.
This study, for the first time, shows that transplantation of non-autologous mitochondria from healthy skeletal muscle cells into normal cardiomyocytes leads to short-term improvement of bioenergetics indicating “supercharged” state. However, over time these improved effects disappear, which suggests transplantation of mitochondria may have a potential application in settings where there is an acute stress.
Outlining Some of the Science Behind Partial Reprogramming at Turn.bio
Turn.bio is an early venture in the new field of in vivo cellular reprogramming, though it is unclear as to whether the partial reprogramming approach they are taking will eventually be used directly in patients, versus in cell cultures prior to transplantation for cell therapy. The publicity materials here cover some of the work undertaken by one of the scientific founders of Turn.bio in recent years, including the transplantation of partially reprogrammed muscle cells into old mice to restore muscle function.
Cells can be reprogrammed into pluripotent stem cells via expression of a small number of genes – the Yamanaka factors. When applied to old cells, this process has been shown to produce numerous beneficial effects along the way. In cells from old tissues it resets many of the epigenetic changes characteristic of aging, and restores mitochondrial function, for example. So while reprogramming most likely cannot meaningfully address issues such as nuclear DNA damage or accumulated molecular waste that cannot be effectively broken down, even by young cells, it may prove to be a useful basis for therapies to treat aging.
This is all a fairly straightforward proposition when applied to cells outside the body and intended for transplantation. When considering in vivo use, however, the challenge lies in reprogramming to a sufficient degree to produce these benefits, versus reprogramming too much, to the point at which tissue is disrupted and cancer arises. The Turn.bio approach is a partial application of reprogramming, to find the point at which cells are shocked into restoring more youthful function, but not so far as to otherwise change their cell type and function. This is a fine balancing act, likely different for different tissues in the body, and still in a comparatively early stage of development.
Old human cells rejuvenated with stem cell technology
Researchers make induced pluripotent stem cells from adult cells, such as those that compose skin, by repeatedly exposing them over a period of about two weeks to a panel of proteins important to early embryonic development. They do so by introducing daily, short-lived RNA messages into the adult cells. The RNA messages encode the instructions for making the Yamanaka proteins. Over time, these proteins rewind the cells’ fate – pushing them backward along the developmental timeline until they resemble the young, embryonic-like pluripotent cells from which they originated.
During this process the cells not only shed any memories of their previous identities, but they revert to a younger state. They accomplish this transformation by wiping their DNA clean of the molecular tags that not only differentiate, say, a skin cell from a heart muscle cell, but of other tags that accumulate as a cell ages. Recently researchers have begun to wonder whether exposing the adult cells to Yamanaka proteins for days rather than weeks could trigger this youthful reversion without inducing full-on pluripotency. In fact, researchers found in 2016 that briefly expressing the four Yamanaka factors in mice with a form of premature aging extended the animals’ life span by about 20%. But it wasn’t clear whether this approach would work in humans.
wondered whether old human cells would respond in a similar fashion, and whether the response would be limited to just a few cell types or generalizable for many tissues. They devised a way to use genetic material called messenger RNA to temporarily express six reprogramming factors – the four Yamanaka factors plus two additional proteins – in human skin and blood vessel cells. Messenger RNA rapidly degrades in cells, allowing the researchers to tightly control the duration of the signal. The researchers then compared the gene-expression patterns of treated cells and control cells, both obtained from elderly adults, with those of untreated cells from younger people. They found that cells from elderly people exhibited signs of aging reversal after just four days of exposure to the reprogramming factors. Whereas untreated elderly cells expressed higher levels of genes associated with known aging pathways, treated elderly cells more closely resembled younger cells in their patterns of gene expression.
When the researchers transplanted old mouse muscle stem cells that had been treated back into elderly mice, the animals regained the muscle strength of younger mice, they found. Finally, the researchers isolated cells from the cartilage of people with and without osteoarthritis. They found that the temporary exposure of the osteoarthritic cells to the reprogramming factors reduced the secretion of inflammatory molecules and improved the cells’ ability to divide and function. The researchers are now optimizing the panel of reprogramming proteins needed to rejuvenate human cells and are exploring the possibility of treating cells or tissues without removing them from the body.
A Short Commentary by Reason from the Giant Health Conference in 2019
I had quite forgotten about the video of this short commentary I’d given last year at Giant Health in London. I was recently prompted for a transcript by someone, and so here it is. This conference was a mainstream health event, not normally a place that would have any great focus on longevity and aging. However, the Aikora Health principals had claimed one of the stages and put together a set of presentations from various people involved in the development of means to treat aging, myself included. All of us were ambushed by interviewers with cameras at some point in the proceedings, and hence this video.
Longevity research and gene therapy: where are we now?
Certainly this event is an example of some of the people in our longevity community coming in and just taking over a little bit of somebody else’s conference to talk about longevity … but really exposing the rest of the community to it. I’m finding that at every event I go to, I’d really love to have conference presentations where I get to talk about some interesting thing about the longevity industry, because there are a lot of really interesting things going on.
But every presentation turns out to be “hey, we exist, please notice us – because this is really, really important.” Everything that you guys think that you are doing in medicine is about to be up-ended, because suddenly we’re going to be actually able to stop people from getting sick and incapacitated and debilitated in old age. This is happening right now, the first rejuvenation therapies exist. But nobody notices.
It is that interesting, weird stage of development where a thing has happened, but not everybody yet realizes that it has happened, and there is an awful lot of advocacy still needed to shove this great idea down everyone’s throats, make them pay attention. That in fact, actually, yes, 50% of everyone with arthritis in old age probably do not need to have arthritis. They could go take a $100 senolytic drug combination and it would go away. This is news to you, and it is news to most people here. It needs to not be news and people need to get on and do this.
Since I run a gene therapy company, it is nice to see a whole gene therapy stage talk about that topic. Gene therapy is very much a wave. When we started Repair Biotechnologies, before we even knew what we were going to do, we said “this will be a gene therapy company.” This is because it is self-evidently the case that a lot of small molecule development is going to go away and be replaced by gene therapy. Gene therapy is more precise, you can do more with it, and it is definitely easier to evolve a gene therapy program than a small molecule program. So this part of the field is really important, and it is really important that more people get out and talk about this.
Macrophages as Both Friends and Foes in Age-Related Diseases
Macrophages are cells of the innate immune system, found throughout the body, and which play a great many roles beyond the obvious ones of defending against invading pathogens. They destroy cancerous and senescent cells, ingest molecular waste and debris between cells, and participate in the processes of tissue regeneration and maintenance, to pick a few examples. Further, the immune system of the brain includes an analogous population of cells known as microglia, which additionally take on supporting roles essential to the proper functioning of neurons and their synaptic connections.
Chronic inflammation is important in the progression of age-related diseases, and as a part of the immune system macrophages are very much involved in inflammation. This is a two-way street; greater inflammatory signaling in the environment will tend to make macrophages adopt a more aggressive behavior, adding their own inflammatory signaling to the mix. Equally, macrophages that become inflammatory for other reasons can rouse greater and broader inflammation via their actions. This is particularly true for senescent microglia, which appear quite important in a number of age-related conditions.
Setting aside cellular senescence, macrophage behavior can be loosely divided into phenotypes known as polarizations. M1 macrophages are inflammatory and focused on attacking pathogens, while M2 macrophages are anti-inflammatory and focused on regeneration. This is a useful categorization, while recognizing that it perhaps oversimplifies the reality of a continuous distribution of behaviors, not a pair of widely separate states. Some aspects of aging are associated with a shift in populations to favor M1 over M2, but this is not universal. Nonetheless, a number of research groups are working to find ways to bias macrophages to one polarization over another, to turn their contribution from harmful to helpful.
Targeting Macrophages: Friends or Foes in Disease?
Macrophages occupy a prominent position during immune responses. They are considered the final effectors of any given immune response since they can be activated by a wide range of surface ligands and cytokines to acquire a continuum of functional states. Macrophages are involved in tissue homeostasis and in the promotion or resolution of inflammatory responses, causing tissue damage or helping in tissue repair.
Knowledge in macrophage polarization has significantly increased in the last decade. Biomarkers, functions, and metabolic states associated with macrophage polarization status have been defined both in murine and human models. Moreover, a large body of evidence demonstrated that macrophage status is a dynamic process that can be modified. Macrophages orchestrate virtually all major diseases – sepsis, infection, chronic inflammatory diseases (rheumatoid arthritis), neurodegenerative disease, and cancer – and thus they represent attractive therapeutic targets. In fact, the possibility to “reprogram” macrophage status is considered as a promising strategy for designing novel therapies.
Macrophages are widely distributed throughout the tissues and display a huge functional heterogeneity. They can acquire pro- or anti-inflammatory functions depending on the surrounding cytokines and tissue microenvironment. Macrophages have been classified according to a linear scale, on which M1 macrophages represent one extreme and M2 macrophages represent the other.
Macrophage polarization is plastic and reversible. While M1 polarization takes place at the initial stages of the inflammatory response, M2 polarization is predominant during resolution of inflammation. The sequential occurrence of both polarization states is an absolute requirement for the appropriate termination of inflammatory responses, as well as for adequate tissue repair after injury, and alterations in the shift between macrophage polarization states result in chronic inflammatory pathologies, autoimmune diseases, and even metabolic disorders. We believe that targeting macrophage polarization might lead to novel intervention strategies.
On the Prospects for Intermittent Late-Life Use of Rapamycin
Researchers here discuss the evidence for intermittent use of rapamycin, an mTOR inhibitor that has undesirable side-effects, to be a path forward to producing benefits in older people. We should probably weigh the animal evidence for this class of therapy against the recent failure of a phase III trial for a related form of mTOR inhibition designed to bypass the side-effects of rapamycin. The beneficial effect sizes in humans may be too small to be worth the cost and time of development at the end of the day, and this is somewhat characteristic of interventions, such as mTOR inhibition, that upregulate cellular stress responses such as autophagy. The effect sizes scale down with increased species life span. This is perhaps best illustrated by calorie restriction, an intervention that also acts through increased autophagy. While the practice of calorie restriction can extend life span by up to 40% in short-lived mice, it adds a few years at best in long-lived humans.
Rapamycin is arguably the best-studied pharmaceutical intervention for reliable lifespan and healthspan extension in a wide array of model organisms. These consistent results are encouraging for those eager to develop interventions for prolonging human lifespan or healthspan. Until recently publications of rapamycin treatment in animal models focused on near lifelong treatment, a scenario that is unrealistic to apply to improving the human condition. However, this is beginning to change. A few groups have endeavored to address this by administering rapamycin to mammalian model organisms beginning at mid- to late-life. Results so far have been encouraging – even when delivered late in life, rapamycin can improve both health- and lifespan in mice.
To bring the field even closer to a limited duration regimen that continues to benefit the organism in late life, some groups have published that both intermittent or transient rapamycin treatment can improve lifespan or organ function. Our own work has demonstrated that 8 weeks of rapamycin delivered late in life in mice can confer an improvement in diastolic heart function. This effect persisted for a further 8 weeks post-treatment, even after the metabolic changes due to acute treatment reverted back to pre-treatment levels. That rapamycin could be useful for larger mammals was given credence through a study of dog cardiac outcomes: 10 weeks of rapamycin administered to middle-aged companion dogs was sufficient to improve measures of both systolic and diastolic cardiac function.
A critical goal of any pharmaceutical treatment is to minimize off-target effects. Rapamycin’s use in the clinic has been extensive, and side-effects have been reported, though they generally resolve when the drug is removed. Efforts to reduce these off-target responses in humans have ranged from co-treatment with another drug, reducing the dose of rapamycin, and changing the dosing schedule to a more intermittent or transient one. Altering the delivery of rapamycin from continuous to intermittent may help in animal models as well; it was found that the positive effects of an intermittent rapamycin treatment can be separated from its side effects. At 2mg/kg per day, every five days, beginning at 20 months of age in mice, rapamycin could increase medial and maximal lifespan without detrimental effects on glucose homeostasis. This was also in the absence of metabolic effects seen in models using higher/longer-term doses of rapamycin. Intermittent treatment may, therefore, help to balance the minimization of off-target effects with the desired continual boost to health-span.
Trajectories of Exercise and Mortality in Late Life
Greater physical activity correlates well with lower mortality in later life. Given the way that human data is collected, and the way in which epidemiological studies are carried out, it is hard to determine causation, however. Is it that exercise is protective, or is it that more robust people both live longer and exercise more often? Fortunately the equivalent animal studies on exercise are unambiguous, and show that exercise does in fact act to improve long-term health and reduce premature mortality. Here, researchers expand on the existing evidence by focusing on trends in physical exercise in later life, and how those trends correlate with mortality. They find the expected outcome, in that a reduction in exercise over time is worse than the alternatives.
Lifelong physical activity (PA) promotes a wide range of health benefits and has long been recognized as an important protective factor for chronic diseases. These beneficial effects consistently translate into lower mortality rates in both men and women. The salutary effects of PA might extend to late life, as it is known to delay the onset of disability and to increase lifespan. Furthermore, PA might be negatively associated with other adverse outcomes such as hospitalization, thereby reducing health care expenditure. Remarkably, at advanced ages, PA levels might surpass other cardiovascular or sociodemographic risk factors that are classically associated with adverse outcomes in younger cohorts.
A common methodological limitation in exploring the association between PA and adverse outcomes in older populations is the use of a single time-point assessment of PA (primarily the baseline PA levels) as the exposure variable, which does not account for the dynamic nature of PA behaviours. It is plausible that prospective trajectories (patterns) of PA levels along time in late life may influence adverse outcomes distinctly as compared with cross-sectional estimates, a hypothesis that remains untested to our knowledge. The main aim of this study is to investigate the existence of different PA trajectories within the Toledo Study of Healthy Aging (TSHA) sample, a Spanish longitudinal population-based study, and to evaluate their associations with adverse outcomes (mortality, disability onset and worsening, and hospitalization).
We found four PA-decreasing and one PA-increasing trajectories: high PA-consistent (n = 566), moderate PA-mildly decreasing (n = 392), low PA-increasing (n = 237), moderate PA-consistent (n = 191), and low PA-decreasing (n = 293). Belonging to the high PA-consistent trajectory group was associated with reduced risks of mortality as compared with the low PA-decreasing group (hazard ratio (HR) 1.68) and hospitalization compared with the low PA-increasing and low PA-decreasing trajectory groups (HR 1.24 and HR 1.25, respectively) and with lower rates of incident (odds ratio (OR) 3.14) and worsening disability (OR 2.16) in relation to the low PA-decreasing trajectory group and at follow-up. Increasing PA during late life (low PA-increasing group) was associated with lower incident disability rates (OR 0.38) compared with the low PA-decreasing group, despite similar baseline PA.
Abnormal Stress Granules in Aging and Age-Related Disease
This open access review paper looks at stress granules in the context of aging. These are transient structures that form within cells, made up of a wide variety of biomolecules. There is a lot of information about stress granules in the literature, but a great deal of it is speculative. This is one of the less well explored areas of cellular biochemistry. Cells form these assemblies of under stressful conditions, and their function may be protective – perhaps a way to stash useful molecules and protect them from an aggressive upregulation of cellular maintenance activities, or perhaps a way to make those useful molecules more available to needed locations in the cell by putting a stockpile in close proximity.
There is evidence for stress granules to become abnormal in the cells of aged tissues, and this may be due to raised levels of misfolded or otherwise broken proteins and other forms of molecular waste. Whether the consequences are significant in comparison to other, better explored mechanisms of aging remains to be determined.
Stress granules (SGs) are membraneless assemblies. They form when cells experience stress conditions, and are thought to influence cellular signaling pathways, and mRNA function, localization, and turn over SGs are dynamic, complex, and variable assemblies, with composition and structure that can vary dramatically under different types of stresses, such as heat shock, oxidative stress, osmotic stress, nutrient starvation, and UV irradiation. SGs have two distinct layers with different components, functions, and dynamics: a stable inner core structure surrounded by a less dense shell layer. The components in the core structure are believed to be less dynamic, while the components in the shell layer are more dynamic.
Severe stress- and aging-related misfolded proteins could specifically accumulate and aggregate within SGs, which could alter SG composition, impair SG dynamics, and, finally, lead to aberrant conversion from a liquid-like to a solid-like state. Under mild stress conditions or normal growth conditions, the cellular chaperone machinery and degradation systems are sufficient to manage the surveillance of such aberrant interactions between RNA-binding proteins (RBPs) and other aggregation-prone proteins. In young cells, multiple cellular defense systems can protect the cells from being affected by damaging changes such as imbalanced cellular proteostasis and proteolysis, inappropriate covalent modifications, and lowered pH levels. In aged cells, however, age-dependent breakdown of such systems may lead to defects in maintaining normal SG assembly, dynamics, disassembly, and clearance. This in turn could lead to the subsequent onset of a barrage of diseases.
Further in-depth investigations will help to reveal the mechanisms underlying the interactions between SGs and aging. First of all, what are the components of SGs formed under chronic stress caused by aging-induced intracellular environmental changes? Dynamic analysis of changes in the properties of SGs and SG components during the aging process could provide vital clues on how aging influences SG formation. Whether these changes exert a synergistic effect that could accelerate aging will be an important question to be answered.
Moreover, it is known that aggregation-prone proteins can be recruited to SGs and that this could result in aberrant or persistent SGs during cellular stress and after the stress subsides. These aberrant SGs might induce a series of effects that can be attributed to reduced stress resistance with age. Such aberrant SGs may also act as seeds to facilitate the formation of irreversible mature protein aggregates in aged cells, further accelerating the decline of the cellular functions of these proteins. Thus, it seems that maintaining a proper SG dynamic might be a potential strategy to delay aging and increase lifespan. Two key questions that remain to be answered are as follows: (a) What kind of proteins are prone to form aggregates during aging? And (b) is aggregation triggered by interactions between aggregation-prone proteins and SG components?
Protein Acetyltransferases Influence Longevity in Short-Lived Laboratory Species
Over the past twenty years a great deal of work has gone into the investigation of protein deacetylases, such as SIRT1, in the context of aging and longevity. Here, researchers note some of the evidence for the other side of the coin, protein acetyltransferases, to also influence life span in short-lived laboratory species. It seems plausible that interventions based on these mechanisms will also produce negligible effects once attempted in humans: all of these metabolic manipulations appear to scale down in their benefits as species life span increases. Treatments that make nematode worms live twice as long typically have little to no useful outcome in humans. This isn’t a part of the field that is likely to produce meaningful treatments for aging, judging by the work taken place to date.
The level of acetylation on a given protein is the result of a balance in the activity of opposing families of enzymes, protein lysine acetyltransferases that attach the acetyl moieties and protein deacetylases that remove the acetyl groups. The idea that protein acetylation plays an important role in the regulation of aging began with the pioneering work on the sirtuin family of NAD+-dependent protein deacetylases. Studies in model organisms such as, flies, worms and mice, showed that genetic or pharmacological modulation of sirtuin activity influenced lifespan. While a role for protein deacetylases in aging is firmly established, the enzymes on the other side of the equation, the protein lysine acetyltransferases, have not received a proportionate share of research into understanding their potential roles in the regulation of aging.
Protein N-ε-lysine acetyltransferases (KATs) are a diverse family of enzymes. While many of these enzymes were originally identified as histone acetyltransferases, it is now clear that most, if not all, have multiple substrates. From a broad perspective, it is not surprising that KATs are likely to play key roles in the aging process. KATs modify proteins involved in many cellular processes including those linked to the hallmarks of aging.
Recent studies have now shown that several KATs are directly linked to the aging process and that genetic and pharmacological manipulation of KATs can influence lifespan. Our understanding of the link between KATs and aging clearly has a long way to go to match our understanding of sirtuins. Important questions that need to be addressed include determining the relevant aging-related cellular processes that each KAT functions in and identifying aging-relevant substrates for each KAT. It will take intensive investigation to decipher the molecular mechanisms underlying the influence of KATs on aging and lifespan.
Is There a Causative Role for Infectious Organisms in Alzheimer’s Disease?
The consensus position on the role of amyloid-β as a meaningful cause of Alzheimer’s disease is under attack. Removal of amyloid-β from human brains has so far failed to reverse or even meaningfully slow the condition, though there are certainly scenarios under which amyloid-β aggregates can be both a contributing cause of Alzheimer’s and a poor target for therapy. For example, amyloid-β aggregation might generate sufficient cellular senescence and inflammation in microglia for that pathology to become self-sustaining even when the amyloid-β is later removed. Alternatively, rising levels of amyloid-β might be a side-effect of persistent infections that generate both chronic inflammation and microglial dysfunction sufficient to advance the disease. That second hypothesis, that Alzheimer’s is the result of microbial infection, is emerging as the primary challenger to the established amyloid cascade view of the condition.
The infectious theory of Alzheimer’s disease (AD) was first proposed some 30 years ago. Since then, the idea has encountered considerable resistance in the research community. Until recently, it had been largely displaced in favor of approaches based on the amyloid hypothesis, the leading theory of Alzheimer’s, which identifies plaques of amyloid beta and tangles of tau protein as underlying drivers of the disease. The research landscape for AD, however, may be changing. The repeated failures of amyloid-targeting drugs along with recent discoveries supporting a microbial link to AD have generated fresh interest in this unorthodox approach.
Even before the amyloid hypothesis came under attack as a potential blind alley, alternate theories of the disease had been proposed. Perhaps Alzheimer’s is caused not by accumulations of inanimate protein but rather by microorganisms, the way so many infectious diseases are. Researchers have used large data sets in order to explore the prevalence of two common herpesviruses sometimes found in Alzheimer’s brain tissue. The study demonstrated that three viral strains appeared in greater abundance in brain samples derived from Alzheimer’s patients, compared with normal brains. The viruses also seem to be implicated in the AD-related genetic networks associated with classic Alzheimer’s pathology, including cell death, accumulation of amyloid-β and production of neurofibrillary tangles.
The pathogen theory has met with some hostility. Researchers may have insufficient background in microbiology or may inaccurately associate infectious agents solely with acute rather than chronic afflictions, though a number of microbial infections can indeed linger in the body asymptomatically for decades. Perhaps the greatest resistance to the pathogen theory comes from proponents of the amyloid hypothesis, some of whom believe that it will diminish research into amyloid plaques and tau tangles. A microbial link with AD and the amyloid hypothesis may be complementary rather than exclusionary, however. It is still possible that deposition of amyloid instigates a process of neurological decline, followed by opportunistic infections, or that the reverse is the case, with amyloid deposits representing a defense response to infection, trapping invasive microbes in sticky concentrations of amyloid.
Loss of Mitochondrial Function with Age in Monocytes may Contribute to the Development of Atherosclerosis
Macrophage cells are derived from circulating monocytes, and, among many other tasks, are responsible for clearing out lipid deposits from blood vessel walls. The conventional view on the age-related nature of atherosclerosis, the build up of fatty deposits that narrow and weaken blood vessels, is that macrophages are vulnerable to oxidized lipids, particularly oxidized cholesterols such as 7-ketocholesterol. These oxidized lipids are far more prevalent in older people, a consequence of the cellular damage of aging. Macrophages in old tissues are overwhelmed by oxidized lipids and become inflammatory, dysfunctional foam cells, and then die, adding their debris to a growing atherosclerotic plaque.
Researchers here argue that the well known decline in mitochondrial function found in all tissues also affects the behavior of monocytes and macrophages in significant ways. Thus loss of mitochondrial function may make a meaningful contribution to the development of atherosclerosis, and methods of restoring mitochondrial function may help to slow the onset of the condition by making macrophages more resilient to the aged environment. As ever, determining the relative size of different contributing mechanisms is a challenging process. The only practical way forward is to put a halt to each different mechanism in isolation, and then observe the results.
Age-related changes at the cellular level include the dysregulation of metabolic and signaling pathways. Analyses of blood leukocytes have revealed a set of alterations that collectively lower their ability to fight infections and resolve inflammation later in life. We studied the transcriptomic, epigenetic, and metabolomic profiles of monocytes extracted from younger adults and individuals over the age of 65 years to map major age-dependent changes in their cellular physiology.
We found that the monocytes from older persons displayed a decrease in the expression of ribosomal and mitochondrial protein genes and exhibited hypomethylation at the HLA class I locus. Additionally, we found elevated gene expression associated with cell motility, including the CX3CR1 and ARID5B genes, which have been associated with the development of atherosclerosis.
Furthermore, the downregulation of two genes, PLA2G4B and ALOX15B, which belong to the arachidonic acid metabolism pathway involved in phosphatidylcholine conversion to anti-inflammatory lipoxins, correlated with increased phosphatidylcholine content in monocytes from older individuals. We found age-related changes in monocyte metabolic fitness, including reduced mitochondrial function and increased glycose consumption without the capacity to upregulate it during increased metabolic needs, and signs of increased oxidative stress and DNA damage.
Natural Killer Cells May Act to Reduce Neuroinflammation
Researchers here provide evidence for natural killer cells to act to reduce inflammation in the brain. This is of interest because chronic inflammation in brain tissue, neuroinflammation, is a prominent feature of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. If a natural mechanism that suppresses inflammation can be harnessed, it might be possible to slow or reverse neurodegenerative conditions, given that inflammation appears to play such a significant role in their progression. That said, recent work on cellular senescence in the supporting cells of brain suggests that selectively eliminating those senescent cells, and thus their inflammatory signaling, via senolytic therapies might be a more direct and near term approach than further attempts at the manipulation of mechanisms involved in the resolution of inflammation.
Natural killer (NK) cells provide the first line of defense against invasion or a virus and are equipped with activating receptors that can sense cellular stress and identify cells that have been altered due to infection. A new study highlights that NK cells act not only as efficient scavengers that attack an intruder but may be critical for regulating and restraining inflammation of brain tissue and protein clumping – hallmarks of Parkinson’s and other neurodegenerative disorders. The report also found that NK cell depletion in a mouse model significantly exaggerated the disease condition. This led to the discovery that, without NK cells, the nervous system was left vulnerable to attack.
“We believe that NK cells exert protection by their ability to reduce inflammation in the brain and clear proteins that misfold and create toxic clumps. In their absence, proteins were left unchecked, and we saw a substantial decrease in viral resistant cells, confirming that NK cells are a major source of signaling proteins that boost the immune system response.”
Researchers are quick to caution that the Parkinson’s work was done in animal models, but are optimistic about future immunotherapy discoveries. Recent human trials that tested immunotherapies against an aggressive form of brain cancer called glioblastoma, indicating that NK cells contribute to elimination of tumor cells and release messages in support of defense of the immune system. Parkinson’s is no longer considered a brain-specific disease, and researchers increasingly recognize a functional connection between the immune system and central nervous system. Researchers found that, in conditions of chronic inflammation such as Parkinson’s, the blood-brain barrier becomes disrupted, allowing immune cells to channel into the brain. “Understanding how the periphery signals for NKs to patrol for infectious agents, even in the absence of disease, could lead to breakthrough treatments for Parkinson’s disease.”
The Gut Microbiome as a Contributing Factor in Alzheimer’s Disease
The gut microbiome changes with age in ways that provoke chronic inflammation. Beneficial microbial populations decline in number while harmful populations expand. This is likely the result of numerous contributing factors, including dietary changes characteristic of age and the decline of the immune system, but at this point it is a challenge to pin down which of these processes are more versus less important to the overall outcome. It is well known that chronic inflammation drives a faster progression of many of the common age-related diseases, including neurodegenerative conditions. Thus it is expected to find links between the gut microbiome and conditions such as Alzheimer’s disease, as is discussed here.
Factors that may be involved in the development of Alzheimer’s disease are thought to include lifestyle habits. Lifestyle dysregulation may not only lead to Alzheimer’s disease, but also to various other health problems such as dysregulation of the gut microbiota. The composition of symbiotic microorganisms has changed dramatically throughout human history with the development of agriculture, industrialization, and globalization. It is postulated that each of these lifestyle changes resulted in a gradual disappearance of microbial diversity and an increase in their virulence, thus causing the formation of a risk path for Alzheimer’s disease pathogenesis. Changes in the microbial composition throughout history suggest an escalation of the risk of Alzheimer’s disease.
Recent advances in research on the etiology of Alzheimer’s disease suggest that microbiota (oral, nasal, intestinal) dysbiosis during life can lead to a systemic inflammatory response and affect microglia immune response in the brain. More and more experimental and clinical data confirm the key role of intestinal dysbiosis and interaction of the intestinal microflora with the host in the development of neurodegeneration. What is more, over time, the pathological permeability of the intestinal mucosa and blood-brain barrier begins to increase and a vicious circle is formed that irreversibly destroys neurons. It is likely that the convergence of the inflammatory response from the gut along with aging and poor diet in the elderly contributes to the pathogenesis of Alzheimer’s disease.
It is a promising idea for prevention or therapeutic intervention. Modulation of the gut microbiota through a personalized diet or beneficial microflora intervention like probiotics or prebiotics, changing microbiological partners and their products, including amyloid protein, can become a new treatment for Alzheimer’s disease.
Age and Dietary Fat Result in Larger Inflammatory Populations of Gut Microbes
Age-related changes in gut microbe populations provide an important contribution to the chronic inflammation that is characteristic of old age. Beneficial species diminish in number, reducing the production of metabolites that aid in optimal cell and tissue function. Harmful species increase in number, interacting with tissue and the immune system in ways that promote chronic inflammation. Practical approaches to reverse the age-related changes observed in the gut microbiome could be realized quite soon, given the will and funding: some form of fecal microbiota transplant, or intense probiotic treatment, perhaps. The former has been demonstrated to work in animals, improving health and extending life, and is already practiced for human patients in the medical community in order to treat certain conditions in which pathological bacteria have contaminated the gut.
Numerous studies have suggested that the composition of the gut microbiota differs between obese and normal weight individuals. However, the cause-effect relationship between obesity and gut microbiota composition is not yet fully understood. This study investigated the short-term responses of the gut microbiota composition to diets with different fat contents. Experimental animals were fed either a a normal diet (ND) or a high-fat diet (HFD) for 20 weeks and the microbial composition was evaluated at 10 and 20 weeks. In agreement with previous studies, body weight and the expression of colonic cytokines increased with higher dietary fat content. The diversity of the gut microbiota was significantly influenced by both age and diet, and two variable showed significant interactions.
At the phylum level, the proportion of Actinobacteria was significantly associated with dietary fat content, while the proportions of Firmicutes and Bacteroidetes were strongly associated with age. In the present study, a HFD significantly elevated the proportions of the phylum Actinobacteria and the class Actinobacteria_c in a positive association with body weight, which have also been shown to be increased in obese subjects and patients with type 2 diabetes.
A growing body of evidence suggests that a HFD increases gut permeability and endotoxemia, resulting in low-grade inflammation and impairment of the gut barrier. Given that bacteria in the phylum Actinobacteria are known as mucin-degrading bacteria, abundant Actinobacteria might be associated with gut barrier impairment induced by a HFD. Indeed, we observed that Actinobacteria was inversely related with tight junction proteins such as E-cadherin and positively associated with proinflammatory cytokines. Therefore, the HFD-mediated increase in Actinobacteria and Actinobacteria_c may play a role in the HFD-induced impairment of the intestinal barrier, leading to colonic inflammation.
We also found that in the phylum Actinobacteria, the class Coriobacteriia and the family Coriobacteriaceae were positively correlated with body weight and proinflammatory cytokines, while the change in the proportions of these bacteria was significantly associated with age. Although the mechanistic effects of age on the Coriobacteriaceae are unknown, it is positively associated with both ROS and inflammatory cytokines, which contribute to metabolic dysfunction.
Arguing for More Computational Modeling to Aid the Transition to Clinical Trials that Target Aging
At some point in the future, clinical trials for therapies that target mechanisms of aging must start to assess the outcome on aging, rather than the present situation in which regulators force potentially broad rejuvenation therapies – such as senolytics – to address only one specific age-related condition at a time. The authors of this paper argue that this will be a challenging transition for present regulatory and research institutions, and that a great deal more use of computational modelling of aging and the effects of interventions will be needed to smooth the way. I agree that the regulatory system is a barrier and a roadblock to the paths that should be taken; I’m not sure that I agree with the specific recommendations made in this paper. Greater effective use of computational modelling should, in principle, allow cost reductions across the board in the development of therapies, but I don’t know that this really changes the nature of the problem beyond reducing the expense of efforts made to solve it.
The conventional paradigm “one disease, one drug” should be updated to achieve the vision of targeting aging as a common component of human diseases. The current deterministic genetic paradigm of diagnosing and treating each separate age-related disease fails to fit with the broader anti-aging strategies aimed to address the closely related concepts of healthspan, resilience, and lifespan, which should be therapeutically managed in the absence of discrete, targetable genetic drivers of aging progression. Perhaps more importantly, current frameworks cannot capture the stochastic aspects that drive the shared trade-offs of the emerging strategies for organismal healthspan and rejuvenation, namely tissue-repair/wound-healing impairment and tumorigenesis.
Successful clinical trials with new families of candidate interventions targeting the biologic machinery of aging per se would be groundbreaking; delaying, preventing (or even reversing) the aging process would result in tremendous cost savings for healthcare systems while increasing the productive contributions that could be made by the older members of our societies. By modeling and predicting the behavior of interventions that target the aging hallmarks in both long-term and acute settings, defined by extension of healthspan/lifespan and enhanced resilience to acute stressors (i.e., reduced frailty), respectively, robust and standardized approaches such as stochastic biomathematical platforms would have the ability to sidestep most of the current challenges in aging-targeting clinical trials, to accelerate the achievement of optimum health and life quality in aging populations.