Fight Aging! Newsletter, December 13th 2021

T-cells are a major component of adaptive immunity, with a high degree of specificity in response to a pathogen challenge, enabling the host to mount a specific immune response and generate immunological memory. Therefore, for effective immune protection against the primary and subsequent challenges, these cells must be maintained in a unimpaired state and appropriately regulated. However, on aging, the immune system undergoes profound changes, loosely termed immunosenescence, that can affect the outcome of the immune response. The impact of these age-related changes on the immune system has been associated clinically with decreased efficacy of vaccines, an increase in the frequency and severity of infectious diseases, and an increased incidence of chronic inflammatory disorders. These alterations are associated with phenotypical and functional changes affecting a variety of immune cells, especially T-cells. It has been shown that chronic stimulation of the immune system, such as by persistent viral infections, associates with age-related alterations in the peripheral T-cell pool. Chronic infection especially by cytomegalovirus (CMV) has a dramatic influence on the T-cell compartment, both on CD8+ and CD4+ T-cells.

In humans, repetitive replication of T-cells is associated with the loss of CD28 and the acquisition of CD57. Thus, CD28- and CD57+ T-cells are considered to be late- or terminally differentiated T-cells characterized by low telomerase activity and shorter telomeres compared with CD28+CD57- T-cells. At least some of these CD28-CD57+ T-cells may be senescent. It has been shown that besides age, persistent CMV infection is also associated with the accumulation of these highly differentiated T-cells. Accumulating evidence supports a detrimental role of senescent T-cells in several chronic inflammatory clinical conditions, including cardiovascular diseases such as atherosclerosis and myocardial infarction.

Our results show that in middle-aged and older overtly healthy individuals, the main factor driving the expansion of CD57+ T-cells is CMV infection. However, from the fourth decade onwards, these cells do not accumulate further with age. In previous work, we showed that the percentage of CD8+CD57+ T-cells was similar between young and middle-aged CMV-seropositive individuals. Therefore, here, we extend our previous findings to show that CD57 expression by T-cells is not only a hallmark of CMV infection in young individuals but also at older ages. Accordingly, once CMV infection takes place, CD57+ T-cells will expand, and after that, their percentage will remain rather stable over time. Thus, our results argue against the consensus that the expansion of these cells is a sign of chronological aging.

Our results regarding CD4+CD57+ T-cell expansions with CMV infection are also in agreement with the observation that CMV, but not aging, has a significant effect on the expansion of pro-atherogenic CD4+CD28- T-cells. These cells (that also express CD57) are cytotoxic, capable of causing vascular damage, and their expansion is associated with autoimmune and cardiovascular disease. Higher frequencies of CD4+CD57+ T-cells have been associated with poorer prognosis in several diseases. In acute heart failure patients, high percentages of these cells are associated with the development of cardiovascular events (defined as heart failure-associated mortality, transplantation, or rehospitalization). In end-stage renal disease patients, the frequency of CD4+CD57+ T-cells is associated with atherosclerotic changes, and in multiple sclerosis, their frequency is associated with disease severity and poorer prognosis.

Therefore, immunological treatments should consider both age and CMV infection as a major factor. This strengthens the need for validation studies with not only the aim to present something novel but also to confirm findings in different populations. The association of these T-cell expansions with CMV infection and disease underlines the necessity of considering CMV serology in any study regarding immunosenescence and emphasizes that the price of immune protection is always some degree of immunopathology.

Even during healthy aging, the functions of the immune system may be weakened by a process known as immunosenescence. Immunosenescence and inflammaging are responsible for the increasing incidence of infections, autoimmune diseases, and neoplasms in the population over 65. Older adults also show weaker responses to vaccination than younger ones. Aging causes adverse changes in the innate and adaptive parts of the immune system, the microenvironment of lymphoid organs where immune cells develop and reside, and the equilibrium of soluble chemokines and cytokines, all responsible for the functioning and homeostasis of the immune system. Aging-associated changes in the primary lymphoid organs, i.e., bone marrow and thymus, have been thoroughly characterized; however, data on aging of the secondary lymphoid organs, e.g., lymph nodes, is still incomplete and requires extensive discussion.

Lymph nodes play a pivotal role in the innate and adaptive immune response to natural antigens and vaccines. Lymphatic vessels direct lymph from the tissues to the lymph nodes scattered throughout the body. As lymph passes through the lymph node parenchyma, antigens come into contact with the effector cells of the adaptive immune system, initiating a cascade of immune processes that enable the recognition and neutralization of foreign antigens and pathogens. Immune cell migration to the lymph node in response to self or foreign antigens exposure relies on the coordinated functioning of adhesion molecules on the surface of leukocytes and venule endothelial cells. Such migration plays a fundamental role in regulating physiological processes, e.g., wound healing and angiogenesis, and pathological phenomena, e.g., inflammation and tumor cell filtration.

The number of lymph nodes in the human body ranges from 300 to 500, and their total weight is about 100 grams. Studies have shown that the number of nodes decreases with age, and aging-associated degenerative features emerge in the lymph nodes, such as fibrosis, lipomatosis, a reduction in the number of postcapillary vessels, and changes in the morphology and function of the specialized endothelial cells lining the venous capillaries. Consequently, the amount of lymphoid tissue in the cortical and medullary zones of lymph nodes is reduced, as is the number and size of germinal centers in lymphoid follicles. These changes result in a reduced reactivity to antigen challenge. The number of follicular dendritic cells also decreases, and the ability to uptake and retain immune complexes is significantly impaired. These deficits result in decreased humoral immunity associated with impaired antibody production in the elderly and an increased susceptibility to infections, one of the leading causes of morbidity and mortality in people over 65

The aging of lymph nodes results in decreased cell transport to and within the nodes, a disturbance in the structure and organization of nodal zones, incorrect location of individual immune cell types and impaired intercellular interactions, as well as changes in the production of adequate amounts of chemokines and cytokines necessary for immune cell proliferation, survival and function, impaired naïve T-cell and B-cell homeostasis, and a diminished long-term humoral response. Understanding the causes of these stromal and lymphoid microenvironment changes in the lymph nodes that cause the aging-related dysfunction of the immune system can help to improve long-term immune responses and the effectiveness of vaccines in the elderly.

The epigenetic clock is an attractive biomarker of aging because it applies to most human tissues, capturing aspects of biological age such as frailty, cognitive/physical fitness in the elderly, age-acceleration in obesity, and lifetime stress. Markers of biological aging represent an important tool to clinically validate the effects of longevity-based interventions. For the first time, these biomarkers of aging give scientists the opportunity to study the effects of anti-aging compounds in real-time and directly in humans. We utilized the TruAge prediction model with Sanger sequencing for DNA methylation analysis. In total, 3 genes including 9 CpG sites were analyzed by the Sanger sequencing. The DNA methylation values obtained for all CpG sites were included in the TruMe age-prediction model (pending publication).

Alpha-ketoglutarate (AKG) is an endogenous intermediary metabolite in the Krebs cycle whose levels naturally decline during aging. AKG is involved in multiple metabolic and cellular pathways. These include functioning as a signaling molecule, energy donor, precursor in the amino acid biosynthesis, and a regulator of epigenetic processes and cellular signaling via protein binding. AKG deficiency in stem cells and progenitor cells increases with age. As animals age, mitochondrial function is progressively impaired and cellular metabolic flux in the mitochondria declines, which exacerbates AKG deficiency. It was reported that AKG increased the lifespan of C. elegans.

Building on these results, AKG (and calcium salt) combined with other Generally Recognized as Safe (GRAS) compounds were studied in mice. The non-genetically altered mouse is the preferred mammalian model to study aging, since the biochemical processes involved in mice aging may apply to other mammals, including humans. In a recent study, sponsored by Ponce de Leon Health and performed at the Buck Institute for Research on Aging, the effect of alpha-ketoglutarate (delivered in the form of a calcium salt - CaAKG) on healthspan and lifespan in C57BL/6 mice was reported. The authors showed that in the mice, AKG reduced frailty and enhanced longevity, indicating a compression of morbidity. These and other discoveries suggest that AKG may be an ideal candidate for pro-longevity human studies.

Herein we report a retrospective analysis of DNA methylation age in 42 individuals taking Rejuvant, an alpha-ketoglutarate based formulation, for an average period of 7 months. DNA methylation testing was performed at baseline and by the end of treatment with Rejuvant supplementation. Remarkably, individuals showed an average decrease in biological aging of 8 years using the TruMe age-prediction model. Furthermore, the supplementation with Rejuvant is robust to individual differences, as indicated by the fact that a large majority of participants decreased their biological age. Moreover, we found that Rejuvant is of additional benefit to chronologically and biologically older individuals. While continued testing, particularly in a placebo-controlled design, is required, the nearly 8-year reversal in the biological age of individuals taking Rejuvant for 4 to 10 months is noteworthy, making the natural product cocktail an intriguing candidate to affect human aging.

David Sinclair - Harvard professor, celebrity biologist, and author of Lifespan - thinks solving aging will be easy. "Aging is going to be remarkably easy to tackle. Easier than cancer" are his exact words, which is maybe less encouraging than he thinks. Sinclair thinks aging is epigenetic damage. As time goes on, cells lose or garble the epigenetic markers telling them what cells to be. Kidney cells go from definitely-kidney-cells to mostly kidney cells but also a little lung cell and maybe some heart cell in there too. It's hard to run a kidney off of cells that aren't entirely sure whether they're supposed to be kidney cells or something else, and so your kidneys (and all your other organs) break down as you age. He doesn't come out and say this is literally 100% of aging. But everyone else thinks aging is probably a combination of many complicated processes, and I think Sinclair thinks it's mostly epigenetic damage and then a few other odds and ends that matter much less.

Epigenetic damage could potentially still be unfixable: how do you convince the thousands of different intermixed cell types in the body to all be the right type again? But Sinclair thinks the body already has a mechanism for doing this: epigenetic repair proteins called sirtuins. Sirtuin activity seems to be regulated by a protein called mTOR, which can be influenced by treatments such as rapamycin, an mTOR inhibitor. The other pill is nicotinamide riboside aka NR (and its close cousin nicotinamide mononucleotide aka NMN). The reactions catalyzed by sirtuins involve nicotinamides, and the more nicotinamides you have, the more effective sirtuins are.

People who are not David Sinclair generally don't expect conquering aging to be this easy. The anti-aging SENS Research Foundation has a list of seven different programs to address what they consider to be seven different causes of age-related damage. This seems more like the "humans are like cars" scenario where you have to fix every part individually and it's really hard. People who are not David Sinclair don't think that nicotinamides are a miracle drug. A well-regarded research center ran a big study on nicotinamides in mice and found that they lived no longer than usual, although they did seem to be healthier in various ways. And people who are not David Sinclair are less enthusiastic about sirtuins, mTOR, and calorie restriction.

My impression of the consensus in anti-aging research is that many people are excited for the same reasons Sinclair is excited, that people are much more optimistic than they were five or ten years ago - but that their level of optimism hasn't quite caught up to Sinclair's level yet.

Research in recent years has convincingly proven that cell senescence is a pathophysiologically relevant cause of age-associated multimorbidity and functional losses. There is good evidence that senescent cells accumulate in essentially all compartments of the skin during ageing, not only in sun-exposed skin but also during intrinsic ageing of sun-protected skin. A recent systematic review finds a significant association between senescent cell abundance in skin and donor age. However, the present knowledge about senescence accumulation during ageing in important cell types in the skin is incomplete and, for some cell types, non-existent.

A study with 9 patients with diabetic kidney disease recently showed that a short systemic intervention with the senolytic combination of Dasatinib and Quercetin can reduce frequencies of senescent cells (assessed as p16INK4a- and p21WAF1/CIP1-positive cells) not only in adipose tissue but also in the epidermis, together with a reduction in circulating senescence-associated secretory phenotype (SASP) factors. However, effects on skin function or quality were not reported.

Interventions aimed at improving aged skin function in humans so far relied on more indirect measures to reduce skin cell senescence. Dermabrasion is known to promote collagen remodeling and re-epithelialisation. In a small study with geriatric volunteers, it reduced frequencies of senescent fibroblasts in the upper dermis, increased papillary thickness, upregulated IGF1 expression and improved the UVB response in sun-protected aged skin. Senescent fibroblasts in the upper dermis were shown to enhance melanin production and drive skin hyperpigmentation in vitro and ex vivo. Accordingly, 10 volunteers with senile lentigo were treated with microneedle radiofrequency for 6 weeks, which reduced both frequencies of p16INK4a-positive cells in the upper dermis and epidermal pigmentation in the treated area.

More recently, a small randomized prospective clinical trial was performed to test whether topical application of rapamycin in low concentration could reduce senescence markers and improve function and appearance of photoaged skin. Topical rapamycin reduced the expression of p16INK4a consistent with a reduction in cellular senescence. This change was accompanied by an improvement in clinical appearance of the skin and histological markers of aging and by an increase in collagen VII, which is critical to the integrity of the basement membrane.

In conclusion, there is a good amount of pre-clinical and clinical data showing a strong positive correlation between reduction of senescent cells frequencies and functional improvement of skin. Whether senescence of skin cells makes a significant causal contribution to skin ageing can still not be conclusively decided, however. Nonetheless, there is strong evidence existing today to assume that better understanding of cell senescence in skin may lead to a breakthrough in interventions into skin ageing.

Recent work has posited a connection between Alzheimer's disease (AD) and isomerization of amino acids in long-lived proteins, which may interfere with lysosomal digestion. Herein, we reanalyzed data originally recorded for global proteomic analysis to look for isomerized peptides, which occur as a result of spontaneous chemical modifications to long-lived proteins. Examination of a large set of human brain samples revealed a striking relationship between Alzheimer's disease (AD) status and isomerization of aspartic acid in a peptide from tau. Relative to controls, a surprising increase in isomer abundance was found in both AD samples.

To explore potential mechanisms that might account for these observations, quantitative analysis of proteins related to isomerization repair and autophagy was performed. Differences consistent with reduced autophagic flux in AD-related samples relative to controls were found for numerous proteins, including most notably p62, a recognized indicator of autophagic inhibition. These results suggest, but do not conclusively demonstrate, that lower autophagic flux may be strongly associated with loss of function in AD brains.

A decline in metabolism and endurance of skeletal muscle is commonly observed in obese patients, but the underlying mechanism is not well-understood. Researchers developed a special obesified mouse model by removing the gene of brain-derived neurotrophic factor (BDNF) exclusively in their skeletal muscle. BDNF is originally identified as an important growth factor for maintaining the survival and activities of neurons. Recent studies have proposed that BDNF is also a muscle-secreted protein (i.e., myokine), but its physiological significance is unknown.

Researchers found that obesity reduced the amount of BDNF in the skeletal muscle of mice. They also observed that the mice without BDNF in their muscle, called 'MBKO' (Muscle-specific BDNF Knockout), gained more body weight and developed worse insulin resistance when the animals were fed with a high-fat diet. In addition, the research team found that MBKO mice have less energy expenditure than their control cohort. The research team further demonstrated that the mitochondria in the muscle of MBKO mice were unable to recycle, leading to the accumulation of damaged mitochondria in the tissues.

Researchers also utilized cultured cell models to pinpoint the molecular mechanism for the defective mitochondrial turnover in BDNF-deficient muscle cells. They found that muscle-secreted BDNF used AMP-activated protein kinase, the well-known energy sensor in cells, to trigger the Parkin/PINK1 pathway for inducing mitophagy (a highly regulated mechanism to recycle the materials in cells in response to various challenges) in skeletal muscle. To extend these findings to therapeutic application, the research team further tested if restoring the BDNF signaling in muscle would rescue the obesity-induced mitochondrial damage. They fed the obese mice with 7,8-dihydroxyflavone, a natural bioavailable BDNF mimetic in plants currently used in the clinical trials of Alzheimer's disease, and found that obesity-induced mitochondrial dysfunction was alleviated.

The aging process can have multiple definitions depending on the perspective from which it is considered. From a biological point of view, the aging process may be defined as the progressive and general deterioration of the functions of the organism that leads to a lower ability to react to changes and preserve homeostasis adaptively. Homeostasis includes all processes that organisms use to actively maintain or adjust to appropriate conditions necessary for survival. Thus, although aging should not be considered a disease (it would be absurd to think of an illness that affects 100% of people), it is the main risk factor for the occurrence of chronic age-related diseases.

There are three physiological systems, the nervous, endocrine, and immune systems, in charge of maintaining body homeostasis. Moreover, these systems are in continuous communication, constituting a neuroimmunoendocrine system, which allows the preservation of homeostasis and, therefore, of health. With aging, there is a functional decline of these homeostatic systems and an impairment in the communication between them, which translates into a worse capacity to mount an adequate response to a variety of stressors. The decay of this capacity, which has also been referred to as decreased homeodynamic space or decreased homeostatic resilience, is what results in higher morbidity and mortality. Nevertheless, the age-related changes in these homeostatic systems are established at different rates in each subject, which translates into a different rate of aging or biological age of individuals with identical chronological age.

We believe that the rate at which these homeostatic systems decline relies on the establishment of a chronic oxidative and inflammatory stress situation. Thus, we describe how the oxidation inflammation theory of aging (oxi-inflamm-aging) is one of the most complete to describe how the process of aging occurs. Even though we are aware that the aging process is multifactorial, we propose mitochondrial reactive oxygen species (ROS) production as the first event involved in this process. In addition, we provide molecular mechanisms that link oxidation and inflammation and demonstrate how immune cells play an essential role in interconnecting both processes and, consequently, modulating the rate of aging. Accordingly, we show how the function and redox state of immune cells can be used as markers of the rate of aging of an individual allowing the prediction of lifespan. Moreover, to further confirm the role of immune cells in the aging process, we show, by modulating the redox and inflammatory state of immune cells and the production of oxidant and pro-inflammatory compounds by these cells, how different situations or conditions, such as the social environment, nutrition, and exercise, can have an impact on the lifespan of the organism.

Aging is characterized by the dynamic remodeling of the immune system designated "immunosenescence," and is associated with altered hematopoiesis, thymic involution, and lifelong immune stimulation by multitudinous chronic stressors, including the cytomegalovirus (CMV). Such alterations may contribute to a lowered proportion of naïve T-cells and to reduced diversity of the T-cell repertoire. In the peripheral circulation, a shift occurs towards accumulations of T-cell and B-cell populations with memory phenotypes, and to accumulation of putatively senescent and exhausted immune cells.

The aging-related accumulations of functionally exhausted memory T lymphocytes, commonly secreting pro-inflammatory cytokines, together with mediators and factors of the innate immune system, are considered to contribute to the low-grade inflammation (inflammaging) often observed in elderly people. These senescent immune cells not only secrete inflammatory mediators, but are also able to negatively modulate their environments. In this review, we give a short summary of the ways that immunosenescence, inflammaging, and CMV infection may cause insufficient immune responses, contribute to the establishment of the hyperinflammatory syndrome and impact the severity of the coronavirus disease 2019 (COVID-19) in elderly people.

Recombinant adeno-associated viruses (rAAVs) are the most commonly used vehicles for in vivo gene replacement therapy and gene editing in preclinical and clinical studies, yet selective transduction of specific tissues after systemic delivery remains a challenge. Recombinant AAVs generated using naturally occurring capsids are predominantly sequestered in the liver after systemic injection. This sequestration limits the efficiency of transduction in other organs and poses a particular challenge for gene delivery to skeletal muscle. Because muscle comprises up to 40% of total body mass, achieving therapeutic thresholds in muscle with natural capsid variants requires extremely high virus doses (~2E+14 vg/kg), which creates a formidable hurdle for vector manufacturing and can result in therapy-limiting toxicity, as observed in some recent clinical trials.

Here, we developed the DELIVER (directed evolution of AAV capsids leveraging in vivo expression of transgene RNA) strategy to combine diverse capsid library generation with stringent transcript-based in vivo selection and to enable directed evolution followed by identification of functional capsid variants in any tissue of interest and any animal model. We apply DELIVER to develop muscle-tropic capsids (MyoAAV) in mice and non-human primates (NHPs) and compare our results to AAV9 and AAVrh74, both of which are naturally occurring AAV capsids currently used in gene replacement trials for Duchenne muscular dystrophy (DMD).

Quantification of in different skeletal muscles of male and female C57BL/6J mice revealed 10 to 29 times higher transgene expression in muscles of MyoAAV-injected compared to AAV9-injected mice. Expression was 6.3 times higher in the heart and 2.8 times lower in the liver of MyoAAV injected animals. Notably, improved transduction efficiency by MyoAAV was restricted to striated muscle tissues, and this engineered capsid variant transduced the lung, kidney, spleen, and brain of injected animals with similar or lower efficiency compared to AAV9. We anticipate that adoption of DELIVER to additional tissue and organ systems will have a far-reaching impact in accelerating the development and translation of gene therapy and other genomic medicine approaches for a variety of human diseases.

Mitochondria are one of organelles that undergo significant changes associated with senescence. An increase in mitochondrial size is observed in senescent cells, and this increase is ascribed to the accumulation of dysfunctional mitochondria that generate excessive reactive oxygen species (ROS). Such dysfunctional mitochondria are prime targets for ROS-induced damage, which leads to the deterioration of oxidative phosphorylation and increased dependence on glycolysis as an energy source. Based on findings indicating that senescent cells exhibit mitochondrial metabolic alterations, a strategy to induce mitochondrial metabolic reprogramming has been proposed to treat aging and age-related diseases.

In this review, we discuss senescence-related mitochondrial changes and consequent mitochondrial metabolic alterations. We assess the significance of mitochondrial metabolic reprogramming for senescence regulation and propose the appropriate control of mitochondrial metabolism to ameliorate senescence. Learning how to regulate mitochondrial metabolism will provide knowledge for the control of aging and age-related pathologies. Further research focusing on mitochondrial metabolic reprogramming will be an important guide for the development of anti-aging therapies, and will provide novel strategies for anti-aging interventions.

Apollo Health Ventures announces the final closing of its second venture fund to build a portfolio of data-driven biotechnology and health tech ventures aimed at extending human healthspan. The oversubscribed Apollo Health Ventures Fund II successfully raised 180 million to invest in both venture creation as well as externally sourced deals.

Advances in understanding the biology of aging coupled with emerging technologies have significantly increased pre-symptomatic detection of age-related damage and dysfunction, paving the way for novel interventions. Apollo Health Ventures' investments focus on companies targeting well-validated aging pathways with the aim of, for example, maintaining overall cellular health and fitness, reducing tissue damage caused by chronic inflammation, or restoring a healthy immune system to provide more resilience and protection against diseases.

Apollo Health's predecessor fund has successfully built and invested in companies developing differentiated therapeutics against age-related disorders demonstrating the firm's leadership and understanding of this therapeutic area. Portfolio companies from the fund include Aeovian Pharmaceuticals, a company developing a safer version of rapamycin, a drug which has been shown to extend healthspan as well as lifespan in several animal models. Apollo has also co-founded Samsara Therapeutics, the world's largest discovery platform developing autophagy-enhancing molecules covering a broad range of therapeutic indications.

Patients with heart failure often have shortness of breath and become fatigued quickly. As people age the number of adverse factors increase, so heart failure primarily affects older people, especially women. Although the symptoms are similar, there are various causes. In one form of the condition the pumping function of the heart is impaired. This can however be improved with widely available medication. In the other form, the heart pumps with adequate force, but the chambers of the heart - the ventricles - fail to fill properly because the ventricular walls become thickened or stiff. There is currently no effective therapy for this form of heart failure.

The mechanics of the heart depend on an elastic giant protein called titin. It is produced by heart muscle cells in distinct variants or isoforms that differ in their flexibility. While very elastic titin proteins predominate in infants, later when growth and remodeling are completed, stiffer titin isoforms are produced to increase pumping efficiency. In heart failure with preserved ejection fraction, thickened heart walls, intercalated connective tissue, and stiffer titin filaments may lead to impaired filling of the ventricles.

"The mechanical properties of titin proteins are difficult to adjust. But we can now intervene in the process preceding protein synthesis - that is alternative splicing. Alternative splicing is a clever trick that nature has devised to create a variety of similar proteins based on a single gene - including the different forms of titin. This process is controlled by splicing factors. One of these, the master regulator RBM20, is a suitable target that we can address therapeutically."

Researcher have found a way to influence RBM20 with antisense oligonucleotides (ASOs). These are short chains of single-stranded nucleic acids that are synthetically produced. They bind specifically to the complementary RNA sequence, the blueprint of the targeted protein, thereby blocking its synthesis. Researchers successfully tested the ASOs in mice with stiffer heart walls. Researchers were able to stabilize the ASOs in such a way that they reach the striated muscles in the mouse model and are not already degraded in the blood, liver, or eliminated by the kidneys. Most of the therapeutic winds up in the heart, with some entering the skeletal muscle. Heart failure is a chronic disease that requires long-term treatment. "So we treated our mice over a longer period of time and were able to see lasting treatment effects."

There is debate to whether cardiovascular health status affects the dose-response association between physical activity (PA) and health outcomes. Studies among patients with cardiovascular diseases (CVDs) found different associations between PA and mortality reductions, which were described as linear, J shaped, or U shaped.

A cohort study (median follow-up 6.8 years) was performed comparing the association between moderate to vigorous physical activity (MVPA) and incident major adverse cardiovascular events (MACE) and all-cause mortality between healthy individuals (n = 112,018), individuals with cardiovascular risk factors (CVRF) (n = 27,982), and CVD (n = 2,493). The shape of dose-response association between MVPA and cardiovascular events and death is curvilinear for healthy individuals and those with CVRF, whereas a linear relationship was found in individuals with CVDs. The association between MVPA and the risk of CVD or mortality is domain specific as leisure activities were associated with the most benefits, nonleisure activities with little benefits, and occupational activities with no benefits.

In conclusion, MVPA is associated with risk reductions in all groups, but, especially, CVD patients should be encouraged that "more is better" regarding PA. PA recommendations could be optimized by taking cardiovascular health status and the domain of MVPA into account.

Physical activity and exercise have long been known to be beneficial to the human body. The benefits of exercise range from being critical for maintaining health and wellbeing, to ameliorating and preventing disease pathogenesis. Exercise has been demonstrated to improve the pathology of several chronic diseases including cardiovascular disease, type 2 diabetes, obesity, and cancer. Regular exercise is now also being "prescribed" at a clinical level as a non-pharmacological therapeutic intervention for complex neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Ultimately this begs the question: Is exercise actually beneficial, or is mammalian physiology not evolutionarily suited to lead a sedentary lifestyle?

Given the broad beneficial effects of exercise observed across disorders of the central nervous system (CNS), it is assumed that exercise provides similar non-pharmacological benefits to retinal degenerative diseases including, but not limited to, diabetic retinopathy (DR), retinitis pigmentosa (RP), glaucoma, and age-related macular degeneration (AMD). These complex neurodegenerative diseases all have varying pathophysiological properties and given these and the limited therapeutic options available, the benefits of exercise in potentially mitigating retinal disease pathologies may be of considerable interest in the field of ophthalmology.

There has been some clinical data that demonstrates both the preventative and rehabilitative effects of exercise to retinal health. Physical activity has been shown to both lower the risk of AMD development and improved visual outcomes. Further, fundamental research into exercise using pre-clinical animal models has demonstrated protection against retinal degeneration including in glaucoma, DR, RP, and AMD. A major question is what is happening at the molecular level in exercise to provide this protection to retinal degeneration? Although the evidence for exercise being of benefit to human physiology is clear, the underlying molecular mechanisms underpinning its benefit, particularly in the CNS, remain largely unknown.