There are two major problems: the eradication of cancer and aging. For radical rejuvenation, gerontologists attempt to activate signaling pathways for rejuvenation/pluripotency. Quite often, such attempts result in the formation of tumors. This happens because the only way is to radically rejuvenate and this normally, without special intervention, leads to cancer. At the same time, oncologists are trying to suppress all these signaling pathways of rejuvenation, based on the idea that tumor cells are the enemies and that they should be eliminated by all available means. In short, this strategy can be called a killing strategy (both through direct action and creating conditions unfavorable for cell growth and proliferation). This currently applied killing strategy does not restore tissue and function deficiency but rather exacerbates it. That is why, after some clinical success, this strategy leads to a recurrence of cancer and the formation of cell clones that are resistant to therapy.

In pregnancy, it is the immune privilege of the fetus that ensures the unidirectionality of the vector totipotency to differentiation, or integrating growth (IG). IG is defined here as the submission of potency of single cells composing an organism to the development program and functions of the whole organism. However, in the adult organism, in the absence of immune privilege, this recapitulation is transformed into cancer, or disintegrating growth (DG).

Cancer cells are normal cells with a blocked entry to the normal growth path and redifferentiation, and the last feature is the only marker of malignant growth. It is this blocking and nonlimited execution of a developmental program in reverse order that is the cause of the disintegrative character of its growth or, in other words, the cause that transforms rejuvenation into DG - not the expression of the so-called oncogenes. Oncogene expression does not affect the normal morphogenetic potential of cells. Oncogenes, as genes that cause cancer, do not exist at all. They are normal genes, due to which organisms are developed and due to which they can potentially reach immortality. All properties that are associated with cancer, except blocked redifferentiation, are features of the embryonic pathway recapitulation and self-renewal, and they are inherent for cells at different stages of ontogenesis.

The transformation of normal cells into tumor cells is an adaptive response to a failure in self-restoration and repair capabilities. Due to the rebirth process, complete tissue renewal leading to the elimination of senescence occurs similarly to embryonic tissue development. We propose to use this potential of transformed cells to eliminate senescence. This will make it possible to direct the process of transformation toward an integrated growth path, to prevent the clinical phenomenon of malignancy and to use the potential of transformed cells to initialize the self-renewal program and program of unlimited life for the whole organism.

Aging is a process and a consequence of processes brought about by steadily increasing restriction of the self-renewal ability, limiting life expectancy, and leading to an increase in the probability of death and, inevitable death resulting from the fading of functions, failure of the regulatory mechanisms, occurrence of endogenous disorders and increased susceptibility to exogenous factors. In our opinion, one of the fundamental (systemic) flaws of gerontology is the idea of the existence of a special aging program and the search for the cause of aging, which states that if removed, aging can be eliminated. However, there is only one general program, a program of growth and development (ontogenesis), of which aging is an integral part. The essence of this program is the stabilization of multicellular integrity by submitting the purposes of the constituent parts (cells) to the purposes of the whole (tissues, organs and the body in entirety), through the epigenetic restriction of cell potencies in favor of perfecting (complicating) tissue specialization, for what we pay for with aging, all types of endogenous pathology and, as a result, mortality.

From this, it follows that the 'cause' of aging is not some special mechanism but a program/order, which can be overridden only by implementing another program, a program, of permanent, unlimited, quantitative and qualitative full restoration of structures, functions and functional interconnections. In other words, the linear unidirectionality of ontogenesis, fatally leading to aging and death, can only be overcome with permanent reontogenesis, through the looping of this linearity. This does not require an application of any force against nature, because similar processes were invented by nature itself and because they work in practically immortal multicellular organisms, such as Hydra vulgaris. It is important to note that Hydra does not have cancer as a pathological process. In other words, a periodic return or 'rollback' to the blast state does not cause cancer (disintegrating growth, DG) in those types of immortal organisms.

During ontogenesis, cells such as neurons or myocardiocytes become postmitotic, thus playing an integrative role in the functioning of an organism. The beginning of the ontogenetic program of development includes its own control of division in relation to cells until its complete stop in postmitotic cells, making them one of the main targets for aging processes. To increase the regenerative possibilities of an organism, it is necessary to make postmitotic cells 'build themselves anew'. The main biological ways to accomplish this is full-scale reprogramming that brings cells back to the early stages of pluripotency. It must be emphasized that what later becomes cancer is initially started as spontaneous reprogramming and the goal is to prevent the transformation of this process into carcinogenesis and direct it as rejuvenation. By creating similar conditions in the body, we can apply safe systemic-induced reprogramming in vivo, without fear of resulting in cancer.

One of the main promoters of age-related disease, such as cancer, is cellular senescence, a process by which cells enter an irreversible cell cycle arrest in response to various stresses. Generally, these cells undergo profound molecular and biological changes, namely decreased genomic stability, increased markers of DNA damage, and induction of the senescent-associated secretory phenotype (SASP). The SASP is a large group of secreted factors that include cytokines, chemokines, angiogenic factors, extracellular matrix-remodeling proteases, and growth factors (e.g. IL-6, IL-8, and TNFα). Despite the protective role that senescence plays in an organism, the accumulation of senescent cells during aging has been associated with many cancers by enhancing neoplastic cell proliferation and metastasis. The most striking evidence supporting a link between senescence and cancer is the fact that removing senescent cells from mice decreases cancer occurrence throughout their lifespan.

The Ras GTPase-activating protein-binding protein 1 (G3BP1), a key factor in the stress response and stress granule (SG) assembly, is associated with several processes including pro-survival response and cell fate. G3bp1-/- mice exhibit a premature aging phenotype as well as symptoms of pathologies related to aging such as ataxia. Since the loss of G3BP1 is associated with age-related phenotypes, it is possible that G3BP1 modulates these effects by controlling cellular senescence and cancer growth.

In this study, we assessed the role of G3BP1 as a regulator of the deleterious effects of senescent cells. We show that G3BP1 is required for the activation of the senescent-associated secretory phenotype (SASP). During senescence, G3BP1 achieves this effect by promoting the association of the cyclic GMP-AMP synthase (cGAS) with cytosolic chromatin fragments. In turn, G3BP1, through cGAS, activates the NF-κB and STAT3 pathways, promoting SASP expression and secretion. G3BP1 depletion or pharmacological inhibition impairs the cGAS-pathway preventing the expression of SASP factors without affecting cell commitment to senescence. These SASPless senescent cells impair senescence-mediated growth of cancer cells in vitro and tumor growth in vivo. Our data reveal that G3BP1 is required for SASP expression and that SASP secretion is a primary mediator of senescence-associated tumor growth.

Mitochondria are cytoplasmic organelles primarily responsible for cellular metabolism and have pivotal roles in many cellular processes, including aging, apoptosis, and oxidative phosphorylation. Dysfunction of the mitochondria has been associated with complex disease presentation including susceptibility to disease and severity of disease. Mitochondrial DNA copy number (mtDNA-CN), a measure of mitochondrial DNA (mtDNA) levels per cell, while not a direct measure of mitochondrial function, is associated with mitochondrial enzyme activity and adenosine triphosphate production. mtDNA-CN is regulated in a tissue-specific manner and in contrast to the nuclear genome, is present in multiple copies per cell, with the number being highly dependent on cell type. mtDNA-CN estimates can be derived from DNA isolated from blood and is therefore a relatively easily attainable biomarker of mitochondrial function. Cells with reduced mtDNA-CN show reduced expression of vital complex proteins, altered cellular morphology, and lower respiratory enzyme activity. Variation in mtDNA-CN has been associated with numerous diseases and traits, including cardiovascular disease, chronic kidney disease, diabetes, and liver disease. Lower mtDNA-CN has also been found to be associated with frailty and all-cause mortality.

Communication between the mitochondria and the nucleus is bi-directional and it has long been known that crosstalk between nuclear DNA (nDNA) and mtDNA is required for proper cellular functioning and homeostasis. However, the precise relationship between mtDNA and the nuclear epigenome has not been well defined despite a number of reports which have identified a relationship between mitochondria and the nuclear epigenome. For example, mtDNA polymorphisms have been previously demonstrated to be associated with nDNA methylation patterns. Further, mtDNA-CN has been previously associated with changes in nuclear gene expression.

Thus, gene expression changes identified as a result of mitochondrial variation may be mediated, at least in part, by nDNA methylation. Further, given that it has been well-established that mtDNA-CN influences a number of human diseases, we propose that one mechanism by which mtDNA-CN influences disease may be through regulation of nuclear gene expression via the modification of nDNA methylation. To this end, we report the results of cross-sectional analysis of this association between mtDNA-CN and nDNA methylation in 5035 individuals from the Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) cohorts.

Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance. Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance. Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

Insilico Medicine announced today that Taisho Pharmaceutical Co., Ltd. and Insilico have entered into a research collaboration to identify novel therapeutics against aging. Insilico Medicine will utilize both the target discovery and generative chemistry parts of its Pharma.AI platform in this collaboration. It will use its proprietary Pandomics Discovery Platform to identify novel targets for senolytic drugs and Chemistry42 platform for a molecular generation. This collaboration brings together Insilico's state-of-art artificial intelligence (AI) technologies in drug discovery with Taisho's expertise in drug development, aimed to extend the human healthspan.

"We're delighted to collaborate with Taisho pharmaceutical, a well-recognized leader in the pharmaceutical industry and healthcare sector. It is believed that aging is a universal phenomenon that we cannot stop. However, emerging scientific evidence has shown that one may be able to reverse some of the age-associated processes. Through this collaboration, we will adopt our AI-powered drug discovery suites together with Taisho's validation platform to explore the new space of anti-aging solutions."

Under the terms of the agreement, Insilico Medicine will receive an upfront payment and milestone payments upon achievement of specified goals. Insilico Medicine will be responsible for early research phase target identification and molecular generation and Taisho will work collaboratively with Insilico in validating the results in various in vitro and in vivo assays. Taisho has the exclusive option to acquire Insilico's co-ownership of the successfully developed programs under agreed payment.

Fusion genes are the abnormal result of an incorrect joining of DNA fragments that come from two different genes, an event that occurs by accident during the process of cell division. If the cell cannot benefit from this error, it will die and the fusion genes will be eliminated. But when the error results in a reproductive or survival advantage, the carrier cell will multiply and the fusion genes and the proteins they encode thus become an event triggering tumour formation. Many chromosomal rearrangements and the fusion genes they produce are at the origin of childhood sarcomas and leukaemias. Fusion genes are also found in among others prostate, breast, lung and brain tumours: in total, in up to 20% of all cancers.

Because they are only present in tumour cells, fusion genes attract a great deal of interest among the scientific community because they are highly specific therapeutic targets, and attacking them only affects the tumour and has no effect on healthy cells. And this is where the CRISPR technology comes into play. With this technology, researchers can target specific sequences of the genome and, as if using molecular scissors, cut and paste DNA fragments and thus modify the genome in a controlled way. In a new study, researchers worked with cell lines and mouse models of Ewing's sarcoma and chronic myeloid leukaemia, in which they managed to eliminate the tumour cells by cutting out the fusion genes causing the tumour.

"Our strategy was to make two cuts in introns, non-coding regions of a gene, located at both ends of the fusion gene. In that way, in trying to repair those breaks on its own, the cell will join the cut ends which will result in the complete elimination of the fusion gene located in the middle." As this gene is essential for the survival of the cell, this repair automatically causes the death of the tumour cell.

In the context of cancer gene therapy, it is clear that targeting a single gene is often insufficient to eliminate cancer cells - yet, many types of cancers are addicted to the presence of a single oncogenic event that can reprogram cells and initiate tumorigenesis. This is the case for the so-called fusion oncogenes (FOs), which are chimeric genes resulting from in-frame fusions of the coding sequences of two genes involved in a chromosomal rearrangement. While the nature of the FOs may be diverse, they are primarily classified as involving transcription factors or tyrosine kinases. Silencing of FO transcripts has been shown to inhibit tumor cell growth in vitro and in vivo, demonstrating FO addiction in many human cancers.

FOs are ideal therapeutic targets for the development of new directed cancer treatments, owing to their cancer-driving roles, their restriction to cancer cells and the reliance of tumors on them. Unfortunately, FOs are challenging to target directly with candidate drugs. The ability to precisely manipulate cancer cell genomes to correct or eliminate cancer-causing aberrations by highly-efficient CRISPR/Cas9 genome editing opens new possibilities to develop FO-targeted options to eliminate cancer cells. In the present study, we describe a simple and efficient genome editing strategy specifically targeting FOs in cancer cells. Our CRISPR/Cas9-based approach induces two targeted intronic double strand breaks in both genes involved in a FO that, importantly, produces a cancer cell-specific genomic deletion that is dependent on the presence of the FO, and has no effect on wild-type gene expression in non-cancer cells.

Periodontitis is a chronic inflammatory disease that affects supporting periodontal tissues surrounding the teeth, i.e., cementum, alveolar bone, and periodontal ligament, leading to extensive tooth loss in severe cases and impacting the systemic well-being of the patient. The understanding of chronic inflammatory disorders, including periodontitis, has been limited to the activation of pro-inflammatory mediators through a canonical pathway that is responsible for the exaggerated synthesis of cytokines such as IL-1β and TNF-α. However, it is now appreciated that the physiology of the inflammatory processes also involves a cascade of programmed and receptor-mediated events that determine the synthesis of endogenous specialized pro-resolving lipid mediators (SPMs), and the resolution of inflammation.

Specialized pro-resolving lipid mediators derived from ω-3 polyunsaturated fatty acids, including resolvins and maresins, have a wide array of functions, induce changes in local biofilm composition, reorganize host response, and enhance bacterial phagocytosis and efferocytosis of inflammatory cells during the immunological responses to microbial and inflammatory stimuli. Resolvin E1 (RvE1), which is derived from eicosapentaenoic acid, has been shown to promote periodontal regeneration inducing the formation of new alveolar bone, cementum, and improved fibrogenesis in an experimental model of periodontitis. Maresin MaR1, which is derived from docosahexaenoic acid, has been shown to have potent activity accelerating surgical wound healing in planaria, providing evidence for organ regeneration and tissue healing. Both RvE1 and MaR1 have the potential to stimulate pro-regenerative activities, regulate wound healing, and reverse tissue destruction.

Thus, we measured the impact of MaR1 and RvE1 in an in vitro model of human periodontal ligament stem cells (hPDLSCs) under stimulation with IL-1β and TNF-α. The data showed that the pro-inflammatory milieu suppresses pluripotency, viability, and migration of hPDLSCs; MaR1 and RvE1 both restored regenerative capacity by increasing hPDLSC viability, accelerating wound healing/migration, and up-regulating periodontal ligament markers and cementogenic-osteogenic differentiation. Together, these results demonstrate that MaR1 and RvE1 restore or improve the regenerative properties of highly specialized stem cells when inflammation is present and offer opportunities for direct pharmacologic treatment of lost tissue integrity.

The human body and its microbiome represent an integrated meta-organism, which results from million years of reciprocal adaptation and functional integration that confers significant advantages for both parties. All the members of this human microbiota participate in host physiology and change according to development and late in the life contributing to health and fitness. The human immune system is influenced by the microbiota assembly, composition, diversity, and dynamics, and the interaction of all these features plausibly contributes to the process of inflammaging. In the last decades, we experienced an explosion of studies on the role of the gut microbiome in health and disease and the relationship between the gut microbiome and the other organs and tissues also due to an improvement of the sequencing methods that can be applied to the study of microbiota.

The complex relationship between humans and the trillions of bacterial cells that form our microbiome remains largely unexplored. The consequences for medicine are challenging, since it is likely that our multifaceted symbiosis affects each aspect of health. Manipulating the intestinal microbiota and microbiome may be helpful for preserving health and treating disease, particularly among older adults. On the contrary, the relationship between the microbiome of other human ecological niches (i.e., oral cavity, lung, skin, vagina, and genito-urinary tract) and the progress of other clinical diseases that are common among older adults remains an important area of future studies. It is also necessary to consider how biological age (assessed by health status and life expectancy) shapes the microbiota and immune system and vice versa. Moreover, the complexity of the interactions within the microbiome of the different body sites and between microbes and hosts presents a major challenge; a more concerted and predictive theoretical framework is imperative to progress.

Efforts to standardize specimen preparation and analytical protocols and to increase the availability of the growing body of data should be increased. These technical efforts as well as robust clinical research will improve characterization of the variation in the global human microbiomes, functions of redundancy, disease biomarkers, immigration, effect of lifestyles, and trajectories of development, all of which will establish the basis to understand the progression from health to disease and to efficiently discover new preventive strategies and therapies.

Olfaction, from an evolutionary aspect, is the oldest of our senses. Across different species, it modulates the interactions between an organism and the surrounding environment even before birth. Nevertheless, the majority of the studies on chemo-sensation have been developed in rodents, with a less rich literature in humans. The incomplete understanding of human olfaction may relate to the complexity of studying the multiple olfactory centers distributed in several brain regions comprising the cortical and the subcortical pathways, e.g., olfactory bulb, piriform and entorhinal cortex, amygdala, orbitofrontal cortex, and hypothalamus. This anatomical heterogeneity implies an extensive connection among the olfactory sensory areas which constitute a complex network essential to associate the olfactory stimulus with other cerebral regions, such as those involved in the processing of memories and emotions and multisensory integration with other senses.

Another challenge facing smell research in humans relates to its minor clinical implication as compared to impairment of vision and hearing: the occurrence of blindness or deafness produces a massive personal and social deficit which severely disrupts someone's life. In line with these observations, the different attention paid to these three senses has been also described, in that older adults in the US received assistance for vision and hearing deficits, whereas no testing for olfactory dysfunction was performed. While vision and hearing have been treated as primary senses for general health, olfaction is gaining increasing importance in clinical settings since its impairment represents an overarching non-invasive biomarker in predicting dementia during aging. With the frequent decline in smell acuity, mostly attributed to the reduced turnover of the olfactory neuroepithelium with aging, the early and pronounced olfactory deficit described in different neurodegenerative diseases, ranging from Alzheimer's to Parkinson's and Huntington's diseases remains yet poorly understood.

In an attempt to put olfaction forward as an early biomarker for pathological brain aging, we draw a comparison with vision and hearing, regarded as more relevant for general health. This perspective article wants to encourage further studies aimed at understanding the mechanisms responsible for the early smell dysfunction in individuals a decade or more before the onset of cognitive symptoms.

Whether a healthy lifestyle impacts longevity in the presence of multimorbidity is unclear. We investigated the associations between healthy lifestyle and life expectancy in people with and without multimorbidity. A total of 480,940 middle-aged adults (median age of 58 years, 46% male, 95% white) were analysed in the UK Biobank; this longitudinal study collected data between 2006 and 2010, and participants were followed up until 2016. We extracted 36 chronic conditions and defined multimorbidity as 2 or more conditions. Four lifestyle factors, based on national guidelines, were used: leisure-time physical activity, smoking, diet, and alcohol consumption. A combined weighted score was developed and grouped participants into 4 categories: very unhealthy, unhealthy, healthy, and very healthy. Survival models were applied to predict life expectancy, adjusting for ethnicity, working status, deprivation, body mass index, and sedentary time.

A total of 93,746 (19.5%) participants had multimorbidity. During a mean follow-up of 7 (range 2-9) years, 11,006 deaths occurred. At 45 years, in men with multimorbidity an unhealthy score was associated with a gain of 1.5 additional life years compared to very unhealthy score, though the association was not significant, whilst a healthy score was significantly associated with a gain of 4.5 life years and a very healthy score with 6.3 years. Corresponding estimates in women were 3.5, 6.4, and 7.6 years. Results were consistent in those without multimorbidity and in several sensitivity analyses. For individual lifestyle factors, no current smoking was associated with the largest survival benefit.

In conclusion, we found that regardless of the presence of multimorbidity, engaging in a healthier lifestyle was associated with up to 6.3 years longer life for men and 7.6 years for women; however, not all lifestyle risk factors equally correlated with life expectancy, with smoking being significantly worse than others.

Injuries in which a peripheral nerve has been completely severed, such as a deep cut from an accident, are difficult to treat. A common strategy, called autologous nerve transplantation, involves removing a section of peripheral nerve from elsewhere in the body and sewing it onto the ends of the severed one. However, the surgery does not always restore function, and multiple follow-up surgeries are sometimes needed. Artificial nerve grafts, in combination with supporting cells, have also been used, but it often takes a long time for nerves to fully recover. Researchers wanted to develop an effective, fast-acting treatment that could replace autologous nerve transplantation. For this purpose, they decided to explore conducting hydrogels - water-swollen, biocompatible polymers that can transmit bioelectrical signals.

The researchers prepared a tough but stretchable conductive hydrogel that contained polyaniline and polyacrylamide. The crosslinked polymer had a 3D microporous network that, once implanted, allowed nerve cells to enter and adhere, helping restore lost tissue. The team showed that the material could conduct bioelectrical signals through a damaged sciatic nerve removed from a toad. Then, they implanted the hydrogel into rats with sciatic nerve injuries. Two weeks later, the rats' nerves recovered their bioelectrical properties, and their walking improved compared with untreated rats. Because the electricity-conducting properties of the material improve with irradiation by near-infrared light, which can penetrate tissues, it could be possible to further enhance nerve conduction and recovery in this way.

Despite an increasing burden of osteoarthritis in developed societies, target discovery has been slow and there are currently no approved disease-modifying osteoarthritis drugs. This lack of progress is due in part to a series of misconceptions over the years: that osteoarthritis is an inevitable consequence of ageing, that damaged articular cartilage cannot heal itself, and that osteoarthritis is driven by synovial inflammation similar to that seen in rheumatoid arthritis. Recent randomised controlled trials, using treatments repurposed from rheumatoid arthritis, have largely been unsuccessful. Genome-wide studies point to defects in repair pathways, which accords well with recent promise using growth factor therapies or Wnt pathway antagonism.

There are many reasons to be optimistic about new therapeutic developments in osteoarthritis. Although it is true that much of what has been learned in the past few years from clinical studies is what not to use in disease, these negative studies have been highly informative in reminding the medical community that osteoarthritis is distinct from inflammatory arthritidies, such as rheumatoid arthritis. Research has shown that inflammation in osteoarthritis is nuanced and that classical immunomodulatory pathways are not good targets, but that there are several other inflammatory pathways awaiting clinical exploration, including those driven by direct mechanical injury of the cartilage (so-called mechanoflammation), complement, and mast cells.

The nature and role of inflammation in osteoarthritis pathogenesis thus remains unclear. Clarification is crucially important, not only so that we can develop appropriate targeted therapies for patients, but also to decide whether patients require stratification before treatment. There has been a popular move to try to phenotype patients, with a view to personalising their treatment to improve the efficacy of a given drug. However, these phenotypes currently lack cohesion, and here is little or no evidence that stratification by any of these features changes the response to treatment.

Clinical successes point towards a focus on regenerative or anabolic pathways rather than inflammatory ones. This fits well with preclinical studies, although the reciprocal relationship between repair and inflammation in the chondrocyte suggests that targeting one will probably affect the other. Recent large genome-wide association studies in osteoarthritis also support the concept that osteoarthritis is a failure of repair. Several at-risk loci have been attributed to genes in the TGFβ and FGF pathways, and there is a notable absence of loci that predict the regulation of classical inflammatory genes. Newer targets identified by genome studies, including the retinoic acid pathway, also look promising.

Can exercise really give older people a longer and healthier life? Generation 100 is the first major study that can tell us that, and researchers have encouraging news. Among most 70-77-year-olds in Norway, 90% will survive the next five years. In the Generation 100 study, more than 95% of the 1500 participants survived. The Generation 100 study is a cause-and-effect study. This means that all participants were divided completely randomly into three different training groups when the study started in 2012.

One group was assigned to do high-intensity training intervals according to the 4×4 method twice a week, while group two was instructed to train at a steady, moderate intensity for 50 minutes two days a week. The participants could choose whether they wanted to train on their own or participate in group training with instructors. The third group - the control group - was advised to exercise according to the Norwegian health authorities' recommendations. This group was not offered organized training under the auspices of Generation 100, but was called in for regular health checks and fitness assessments.

Both physical and mental quality of life were better in the high-intensity group after five years than in the other two groups. High-intensity interval training also had the greatest positive effect on fitness. "In the interval training group, 3% of the participants had died after five years. The percentage was 6% in the moderate group. The difference is not statistically significant, but the trend is so clear that we believe the results give good reason to recommend high-intensity training for the elderly. Among the participants in the control group, 4.5% had died after five years. One challenge in interpreting our results has been that the participants in the control group trained more than we envisioned in advance. One in five people in this group trained regularly at high intensity and ended up, on average, doing more high-intensity training than the participants in the moderate group. You could say that this is a disadvantage, as far as the research goes. But it may tell us that an annual fitness and health check is all that's needed to motivate older people to become more physically active."

Older subjects, men, and those with pre-existing conditions such as hypertension, diabetes, cancer, heart failure, and chronic obstructive pulmonary disease are more prevalent among hospitalized COVID-19 patients. Clinical risk factors for COVID-19-related deaths have been identified using a very large cohort. The most common comorbidities have age as a risk factor and have been described in recent years as age-related diseases. The COVID-19 case fatality rate (CFR), that is, the quotient of deaths to confirmed infections, was shown to be lower in patients below 60 years old (1.4%) compared to those who were 60 years or older (4.5%). The severity of the respiratory illness might be related to age-associated changes in the physical properties of the lung and the decline of the immune function, known as immunosenescence.

In general, the idea that older people are more susceptible to infections is not new. In fact, it has been reported that up to one third of deaths in the elderly is a result of infectious diseases. Persistent viral infections may also trigger monoclonal expansion of T cells, which over the lifetime results in poor variability of memory T cells. In turn, this eventually drives immune exhaustion due to the decline in T-cell diversity, a critical problem when facing novel threats such as SARS-CoV-2.

An additional feature that characterizes the severe cases of COVID-19 is the elevated levels of inflammation that can compromise lung tissue integrity and function, leading to pneumonia. Remarkably, accumulated and exhausted T cells secrete preferentially pro-inflammatory cytokines such as IFN and TNF. These cytokines can contribute, along with the innate immune system, to the low-grade pro-inflammatory background observed in elderly individuals, which may worsen COVID-19 outcomes and explain the elevated levels of inflammation. It is also possible that age-associated clonal hematopoiesis may contribute to the increased inflammation due to hematopoietic stem cell myeloid generation bias of pro-inflammatory macrophages and mast cells, and reduction of lymphoid differentiation.

Moreover, decreased T-cell capacity to properly activate antibody-secreting cells to further elicit effective immune responses may be compromised. Yet, another possible explanation is thymus involution. During aging, the thymus becomes atrophic and is gradually replaced by fibrotic tissue. This results in a reduced number, or even complete abrogation, of exiting naive T cells. Together, all these features may result in the decreased ability of older people to fight viral infections, leading to age-related inflammation and higher susceptibility of the lung, and eventually other organs, to the COVID-19-inflicted damage.

In this work, we revealed a strong link between COVID-19 fatality rate and aging. Based on our analysis, we propose that COVID-19, and more generally deadly respiratory diseases, should be considered as novel and emergent diseases of aging. Understanding that age is a major factor for fatality of COVID-19 may help to design approaches against this disease that target the aging process, along with specific antiviral approaches and those that boost more efficiently the human immune system of the elderly.

We previously identified 529 proteins that had been reported by multiple different studies to change their expression level with age in human plasma. In the present study, we measured the q-value and age coefficient of these proteins in a plasma proteomic dataset derived from 4263 individuals. A bioinformatics enrichment analysis of proteins that significantly trend toward increased expression with age strongly implicated diverse inflammatory processes. A literature search revealed that at least 64 of these 529 proteins are capable of regulating life span in an animal model. Nine of these proteins (AKT2, GDF11, GDF15, GHR, NAMPT, PAPPA, PLAU, PTEN, and SHC1) significantly extend life span when manipulated in mice or fish.

By performing machine-learning modeling in a plasma proteomic dataset derived from 3301 individuals, we discover an ultra-predictive aging clock comprised of 491 protein entries. The Pearson correlation for this clock was 0.98 in the learning set and 0.96 in the test set while the median absolute error was 1.84 years in the learning set and 2.44 years in the test set. Using this clock, we demonstrate that aerobic-exercised trained individuals have a younger predicted age than physically sedentary subjects. By testing clocks associated with 1565 different Reactome pathways, we also show that proteins associated with signal transduction or the immune system are especially capable of predicting human age. We additionally generate a multitude of age predictors that reflect different aspects of aging. For example, a clock comprised of proteins that regulate life span in animal models accurately predicts age.

Researchers mapped the genes of animals that have the ability to regenerate retinal neurons. For example, when the retina of a zebrafish is damaged, cells called the Müller glia go through a process known as reprogramming. During reprogramming, the Müller glia cells will change their gene expression to become like progenitor cells, or cells that are used during early development of an organism. Therefore, these now progenitor-like cells can become any cell necessary to fix the damaged retina.

Like zebrafish, people also have Müller glia cells. However, when the human retina is damaged, the Müller glia cells respond with gliosis, a process that does not allow them to reprogram. "After determining the varying animal processes for retina damage recovery, we had to decipher if the process for reprogramming and gliosis were similar. Would the Müller glia follow the same path in regenerating and non-regenerating animals or would the paths be completely different? This was really important, because if we want to be able to use Müller glia cells to regenerate retinal neurons in people, we need to understand if it would be a matter of redirecting the current Müller glia path or if it would require an entirely different process."

The research team found that the regeneration process only requires the organism to "turn back on" its early development processes. Additionally, researchers were able to show that during zebrafish regeneration, Müller glia also go through gliosis, meaning that organisms that are able to regenerate retinal neurons do follow a similar path to animals that cannot. While the network of genes in zebrafish was able to move Müller glia cells from gliosis into the reprogrammed state, the network of genes in a mouse model blocked the Müller glia from reprogramming. From there, researchers were able to modify zebrafish Müller glia cells into a similar state that blocked reprogramming while also having a mouse model regenerate some retinal neurons. Next, the researchers will aim to identify the number of gene regulatory networks responsible for neuronal regeneration and exactly which genes within the network are responsible for regulating regeneration.