Fight Aging! Newsletter, May 27th 2019

Immunosenescence was initially defined as a group of changes that occur in the immune response during the aging process. The reason for that is the immune system was believed to collapse with the aging process, considering the increased susceptibility of these individuals to infectious diseases and developing cancer, reduced production of antibodies against specific antigens, increase in autoantibodies, decrease in T-lymphocyte proliferation, in addition to thymic involution. However, immunosenescence is currently defined by some researchers as remodeling of the immune system, suggesting plasticity of the immune system in the aging process. According to these researchers, the aging process does not necessarily bring an inevitable decline of immune functions; what happens is a rearrangement or an adaptation of the immune system to adjust the body that has been exposed to different pathogens throughout life. Depending on how successful that rearrangement or adaptation is, senior individuals can reach longevity with quality of life or, conversely, develop chronic diseases (comorbidities) and/or be often hospitalized due to severe infections.

This adaptation of the immune system brought by aging seems to result in reduced number and repertoire of T cells due to thymic involution, accumulation of memory T cells from chronic infections, homeostatic proliferation compensating for the number of naïve T cells, decreased proliferation capacity of T cells against stimuli, T cell replicative senescence and inflammaging, besides accumulation of myeloid-derived suppressor cells (MDSC).

As we get older, during hematopoiesis in the bone marrow, the myeloid lineage tends to increase, which can favor the accumulation of MDSC. These cells are able to suppress T cells proliferation and function, and produce pro-inflammatory cytokines. Moreover, there is thymus involution and replacement of thymic tissue by adipose tissue. Hence, there is reduced T cell receptor (TCR) variability and release of naïve T cells. The decreased thymic release of naïve cells, together with the immune response against infections throughout life, lead to the accumulation of memory T cells. In elderly individuals, both naïve and memory T cells can be maintained thanks to homeostatic proliferation, which shortens the telomeres of these cells, resulting in replicative senescence of T cells that produce pro-inflammatory cytokines, and promote inflammaging. The shortening of telomeres also decreases the proliferation capacity of T cells, which will produce less interleukin-2, further decreasing the proliferation of these cells.

Considering T cells are essential for the adequate response against pathogens and neoplasms, and for protection after vaccination, it seems reasonable that changes in T cells quantity, phenotype, and function play an important role in immunosenescence. By understanding each of the mechanisms originated by remodeling of the immune system brought by aging, we could use the cells addressed in the present study (T cells and MDSC) as early and minimally invasive biomarkers for aging-related diseases. The aim is to minimize the limitations of immunosenescence and ensure better treatment for the vulnerable elderly population.

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.

Ever-growing lifespans are the result of regular advances in medical science. In 1900 the three leading causes of death in the United States were pneumonia/influenza, tuberculosis, and diarrhoea. Only a century and a bit on, many of the major acute illnesses are tractable. Every month brings striking new medical advances. Increasingly, medical research is shifting from acute conditions such as influenza towards chronic conditions including diabetes and Alzheimer's. Ageing is the ultimate chronic condition, and there seems to be no reason, in principle at least, that would prevent us from discovering a means of halting or reversing ageing itself.

What if that all happens sooner rather than later? But what if it's not soon enough? Imagine that, after a few more breakthroughs, a scientific consensus emerges that we will have conquered illness and ageing by the year 2119; anyone alive in 2119 is likely to live for centuries, even millennia. You and I are very unlikely to make it to 2119. But we are likely to make it relatively close to that date - in fact, relative to the span of human history, we've already made it very close right now. Think that through, carefully. What would it mean to realize that you very nearly got to live forever, but didn't? What would it mean if, in our looming senescence, we were increasingly forced to share social space with young people whose anticipated allotment of time massively dwarfs our own? We would then be the last mortals.

To be precise, the kind of immortality I have in mind can be called biological immortality. A biologically immortal organism does not die from illness or ageing - though they may still die in a plane crash. If humans acquired biological immortality, our expected lifespans would jump to enormous lengths. Almost everyone would still eventually die; statistics dictate that if you fly on planes every few weeks for eternity, eventually one will crash. This point allows us to sidestep one of the perennial questions about immortality: is endless life something we'd really want? What is distinctive for biological immortals is that death becomes only a possibility, an option, not an inevitability on a fixed timetable. This sort of immortality, I would think, is definitely not a curse. To have the option of living healthily a very long time, possibly for as long as one could want (but no longer), seems like an unmitigated blessing.

Until now, the wish for immortality was mere fantasy. No one has ever lived beyond 122 years, and no one has reasonably expected to do so. But what happens once the scientists tell us that we're drawing near, that biological immortality will be ready in a generation or two - then what? Seneca told us to meet death cheerfully, because death is "demanded of us by circumstances" and cannot be controlled. Death's inevitability is what makes it unreasonable to trouble oneself. Yet, as I've been arguing, soon death may cease to be inevitable. It may become an option rather than a giver of orders. And, as the fantasy of immortality becomes a reasonable desire, this will generate not only new sorts of failed desires, but also new ways to become profoundly envious.

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."

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.

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.

There is increasing evidence that Parkinson's disease (PD) pathology is accompanied by ongoing inflammatory processess. This neuroinflammatory component is particularly relevant for better understanding disease progression accordingly developing disease-modifying therapies. Therefore, the present study explored dysregulated inflammatory profiles in the peripheral blood cells and plasma of PD patients within the context of established clinical indicators. We performed a screening of selected cell-surface chemokine receptors and adhesion molecules in peripheral blood mononuclear cells (PBMCs) from PD patients and age-matched healthy controls in a flow cytometry-based assay. ELISA was used to quantify VCAM1 levels in the plasma of PD patients.

The present data illustrate the role soluble VCAM1 (sVCAM1) levels may play in PD pathology. The levels of sVCAM1 observed here were even higher than those reported for patients with rheumatoid arthritis, multiple sclerosis, and neuromyelitis optica. Although substantial evidence exists for the association between increased sVCAM1 and age and cognitive impairment, the use of age-matched healthy donors in this study has illustrated that the increase observed in PD is independent of physiological aging. Furthermore, sVCAM1 correlated with both disease stage and the motor aspects of daily living.

Whether elevated sVCAM1 levels actively drive disease progression in PD or are a consequence of it remains to be fully understood. Of note, VCAM1 has already been implicated to be a potential mediator of PD pathogenesis. Thus, whether targeting the VCAM1-VLA4-axis is a viable therapeutic avenue remains to be established. Indeed, promising evidence for the therapeutic potential of the VCAM1-VLA4 axis in age-related pathologies of the central nervous system already exists; it has been shown that blocking VCAM1 slows down normal brain aging, induces neurogenesis, and ameliorates neuroinflammation. Our chemotaxis assay revealed diminished lymphocytic migration in PD patients which may be indicative of compromised cellular adherence and infiltration of endothelial barriers. Therefore, additional investigations and in vivo studies addressing both the expression and functional state of VCAM1 on brain endothelial cells are necessary.

Recently, type 2 diabetes mellitus (T2DM) has been identified as a risk factor for Alzheimer's disease (AD). Epidemiological studies of patient data sets have found a clear correlation between T2DM and the risk of developing AD or other neurodegenerative disorders. In one study, 85% of AD patients had diabetes or showed increased fasting glucose levels, compared to 42% in age-matched controls. In longitudinal studies of cohorts of people, it was found that glucose intolerance was a good predictor for the development of dementia later in life.

When analyzing the brain tissue of AD patients, it was observed that insulin signaling was much desensitized, even in AD patients that did not have T2DM. One study found that the levels of insulin, IGF-1, and IGF-II were much reduced in brain tissue. In addition, levels of the insulin receptor, the insulin-receptor associated PI3-kinase, and activated Akt/PKB kinase were much reduced. A second study found increased levels of IGF-1 receptors and the localization of insulin receptors within cells rather than on the cell surface where they could function.

Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function and replacement, autophagy, oxidative stress management, synaptic plasticity, and cognitive function. Insulin desensitization, therefore, can enhance the risk of developing neurological disorders in later life. Other risk factors, such as high blood pressure or brain injury, also enhance the likelihood of developing AD. All these risk factors have one thing in common - they induce a chronic inflammation response in the brain. Insulin reduces the chronic inflammation response by inhibiting secondary cell signaling induced by pro-inflammatory cytokines. A desensitization of insulin signaling enhances the inflammation response and the desensitization observed in T2DM, therefore, not only compromises growth factor signaling, and energy utilization in the brain, but also facilitates the chronic inflammation response.

A new study finds that protein-truncating variants in the apolipoprotein B (APOB) gene are linked to lower triglyceride and LDL cholesterol levels, and lower the risk of coronary heart disease by 72 percent. Protein-truncating variants in the APOB gene are among the causes of a disorder called familial hypobetalipoproteinemia (FHBL), which causes a person's body to produce less low-density lipoproteins (LDL) and triglyceride-rich lipoproteins. People with FHBL generally have very low LDL cholesterol, but are at high risk of fatty liver disease.

"An approved drug, Mipomersen, mimics the effects of having one of these variants in APOB, but due to the risk of fatty liver disease, clinical trials for cardiovascular outcomes won't be done. Using genetics, we provided evidence that targeting this gene could reduce the risk of coronary heart disease."

The researchers sequenced the APOB gene in members of 29 Japanese families with FHBL. Eight of the Japanese families had protein-truncating variants in APOB, and individuals with one of those variants had LDL cholesterol levels 55 mg/DL lower and triglyceride levels 53 percent lower than individuals who did not have an APOB variant. The researchers also sequenced the APOB gene in 57,973 participants of a dozen coronary heart disease case-control studies of people with African, European, and South Asian ancestries, 18,442 of whom had early-onset coronary heart disease. Again, they found that people with these APOB gene variants had lower LDL cholesterol and triglyceride levels. Only 0.038 percent of the people with coronary heart disease carried an APOB variant, while 0.092 percent of those without coronary heart disease did, indicating that carrying gene variants in APOB reduces the risk of coronary heart disease.

Senescence is a leading cause of age-related cataract (ARC). The current study indicated that the senescence-associated protein, p53, total laminin (LM), LMα4, and transforming growth factor-beta1 (TGF-β1) in the cataractous anterior lens capsules (ALCs) increase with the grades of ARC. In cataractous ALCs, patient age, total LM, LMα4, TGF-β1, were all positively correlated with p53.

In lens epithelial cell senescence models, matrix metalloproteinase-9 (MMP-9) alleviated senescence by decreasing the expression of total LM and LMα4; TGF-β1 induced senescence by increasing the expression of total LM and LMα4. Furthermore, MMP-9 silencing increased p-p38 and LMα4 expression; anti-LMα4 globular domain antibody alleviated senescence by decreasing the expression of p-p38 and LMα4; pharmacological inhibition of p38 MAPK signaling alleviated senescence by decreasing the expression of LMα4. Finally, in cataractous ALCs, positive correlations were found between LMα4 and total LM, as well as between LMα4 and TGF-β1.

Taken together, our results implied that the elevated LMα4, which was possibly caused by the decreased MMP-9, increased TGF-β1 and activated p38 MAPK signaling during senescence, leading to the development of ARC. LMα4 and its regulatory factors show potential as targets for drug development for prevention and treatment of ARC.

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.

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.

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.

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."

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.

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.