How did OneSkin Technologies come about? What led you into cosmetic senolytics?

OneSkin's initial proposal was to validate the effectiveness of "anti-aging" skincare products available in the market, in order to meet the needs of consumers for science-validated products as well for the companies that are looking to differentiate their products from competitors. Our approach for this validation was to test a given molecule in 3D human skin equivalents and analyze changes in the methylation pattern by running age-predictor algorithms, such as the Molecular Clock developed by Steve Horvath in 2013. Since this and other algorithms used at the time largely failed to predict skin age accurately, we decided to develop our own skin-specific molecular clock, in which the average difference between predicted age and chronological age is lower (approximately 4.6 years) than the currently available molecular clocks. Later on, we realized that we could create more value and offer a scalable solution by developing new and more effective products for skin rejuvenation, instead of limiting ourselves to validating third party products. We also realized that there wasn't any initiative for targeting senescent cells focused on our body's largest organ, the skin.

We believe the skin will be the first tissue to benefit from a senotherapeutic approach since it allows for topical application, virtually no contact with the bloodstream, and possibly a faster route to the market, if categorized as a cosmetic. We also love the proposal to develop senotherapeutics for skin because their effects will be visually perceived by consumers. Finally, the International League of Dermatological Societies (ILDS), a global, not-for-profit organization representing 157 dermatological societies worldwide, has identified the consequences of skin aging as one of the most important grand challenges in global skin health. Reduced functional capacity and increased susceptibility of the skin with development of dermatoses such as dry skin, itching, ulcers, dyspigmentation, wrinkles, fungal infections, as well as benign and malignant tumors are the most common skin conditions in aged populations worldwide and may be prevented with the use of technologies that have been designed to promote skin age reversal, like ours.

The audience here is more familiar with the FDA process for new drugs. How does cosmetics development differ from that?

Here in the US, the law does not require cosmetic products to have FDA approval before they go on the market, but there are laws and regulations that apply to cosmetics on the market, including the voluntary cosmetic registration program. Despite the general feeling that cosmetics are hardly regulated by FDA, safety is the number one rule, accompanied by the important observation that cosmetic products must be properly labeled. This means that any cosmetic product in the market should do no harm to the skin. For this purpose, there are guidelines to be followed when introducing a new molecule in a cosmetic product.

Basically, the company should provide data regarding mutagenesis and chromosomal changes by performing tests such as the Ames test (which uses bacteria to analyze the potential of a given compound to cause DNA mutations), cytotoxicity (using human cells) and karyotyping analysis (using human cells). Since OneSkin does not use animals to develop products, additional safety studies using the complete formulation to assess skin irritation, corrosion, and sensitization are performed in human skin equivalents (in vitro) and also in human subjects. Additional tests, such as ocular toxicity are desirable and even mandatory according to the cosmetic product. At OneSkin, we performed most of the cited tests, including cytotoxicity in human fibroblasts and keratinocytes derived from different donors, mutagenesis (Ames) and chromosomal aberration (karyotyping), toxicity through human skin equivalents, and, finally, we have already performed the Repeated Insult Patch Testing (RIPT) in 54 human subjects, provided by an independent contract organization. All of them came out clear and in accordance with the parameters required, guaranteeing safety for our future clients.

Tell us something about your development. What is your candidate molecule, and how far along are you in the process of validation leading to human use?

Our lead candidate molecule is a new synthetic peptide, which was initially screened in a synthetic library for antimicrobial peptides (AMP). AMPs have multifunctional behavior and accumulate several interesting properties for skin applications, including tissue repair, antioxidant activity, collagen synthesis, anti-inflammatory activity and we decided to evaluate their senotherapeutic potential. From our initial 200 library, we selected 4 hits - the 4 compounds which were most effective in decreasing senescent cells in human skin. Then, we used an algorithm to create variations of such sequences, leading to hundreds of possible leads. Among those leads, we selected the two best peptides, deemed OS-1 and OS-2, which have consistently shown the ability to decrease human cellular senescence caused by aging, ultraviolet light, and other types of genotoxic stress by 25-50%.

It is worthy of mention that we chose to build a human cell-based platform in order to close the gap between preclinical and clinical scenarios and to mimic skin aging as closely as possible. Indeed, our valuable technological platform is proprietary and has been patented. To briefly outline our pipeline, first, we evaluate the ability of new compounds to decrease cellular senescence through two markers. The classical senescence associated-β-galactosidase (SA-β-Gal) marker is analyzed, as it has been consistently used in the aging field for a least 30 years and is considered an easily identifiable marker of cellular senescence. Nevertheless, since SA-β-Gal also has important limitations, we complement our analysis with a more recent and sensitive marker of cellular senescence, ATRX foci formation.

For each compound, we test both markers in cells obtained from at least three different healthy and aged donors. As positive controls, we have used senolytic and senomorphic molecules, such as fisetin and rapamycin. We also have tested most of senolytics described in the literature and most have failed to induce apoptosis in senescent cells in those cell types or show nonspecific effects, causing a significant toxicity to non-senescent cells. To date, our peptides are the molecules that have performed the best, considering safety and efficacy endpoints. We have been able to replicate human skin aging in vitro by growing skins with cell donors of diverse ages, ranging from a neonatal (0Y), to young (approximately 30Y) to aged (over 50Y). We have characterized these models according to skin equivalent structural organization, gene expression, and accumulation of senescent cells. Using aged skin equivalents, we test compounds by adding them into the culture media for 5 days. At this time, histological, SA-β-gal staining and qPCR analysis are performed to evaluate the skin health and the senotherapeutic and age reversal potential of such molecules. Additionally, we have formulated our main peptide in a topical cream and have applied onto skin biopsies of aged donors, and we could observe an improvement in epidermal thickness after 5 days of treatment.

Importantly, OS-1 is performing better than retinoic acid, currently considered the gold standard molecule for anti-aging skincare products. It is also worth mentioning that we have consistently seen an increased expression of p16 and inflammatory cytokines like IL-6 and IL-8, along with the "peeling effect" of retinoic acid, which is usually perceived in human use.

Finally, after performing these in vitro studies and clearing the safety (including an IRB approval) of our lead candidate, we have improved our own topical OS-1 formulation and began testing it on a group of 23 healthy volunteers, ranging from 32 to 84 years old. This experiment was initially focused on safety assessment only, but we already consider it a first validation of OS-1 effectiveness in humans, since our preliminary data is extremely promising, with 100% safety and a significant visual improvement observed in most patients within the first month of continuous use. Later this year, we will proceed to a randomized, placebo-controlled clinical study provided by an independent contractor organization.

Why can't one just use dasatinib, or other established senolytics, in some form and spread it on skin? Why something new?

Despite major proofs of concepts generated in the longevity field recently, the clinical use of senolytics must be carefully evaluated. We initially tested several senolytics like dasatinib and unfortunately, the majority that we tested on our platform were either very toxic even to non-senescent cells, or are not effective in decreasing the relative percentage of cellular senescence. Initially, we were disappointed by the lack of reproducibility in our hands, but since we have tested such compounds consistently, we believe that the discrepancies observed may result from different experimental settings, since most papers are based on animal models or genetically-modified cell lines, while we work with healthy and normal aged human cells.

Furthermore, when tested in skin equivalent models, senolytics continued to be highly toxic, compromising skin equivalent general structure, and decreasing the thickness of the epidermis. ABT-263, A1331852 and Dasatinib + Quercetin are but a few senolytics we have already tested. We have tested other molecules which are safer and effective like fisetin, but this molecule has the limitation of requiring high concentration to be effective (i.e. 20 μM), due to its low bioavailability. Fisetin's natural color (yellow to orange) also impairs its use in a topical product.

If your product works topically on skin, why not administer it systemically to clear out senescent cells throughout the body?

As mentioned before, we believe skin health is an important and highly overlooked target to rapidly promote drastic improvement of wellness, self-confidence, and prevention of aging-related skin disorders. Therefore, we have chosen skin as a starting point to validate our lead molecule and start bringing its benefits earlier to consumers. Once OS-1 ́is proven to be well-tolerated and effective at reducing skin senescence when applied topically, it will then open several avenues to explore other indications of the peptide throughout the body, which would fall in the regular FDA pathway for drug development. In this regard, one basic assay we performed in order to assess the potential application of OS-1 for longevity purposes was the evaluation of healthspan improvement and lifespan extension in C. elegans worms. In this experiment, parameters of healthspan (thrashing and esophageal pumping - which basically indicates how well the worm moves and eats) were improved, and the treated worms lived longer (median life extension increased approximately 12%).

This is comparable to other age reversal strategies published in the literature, and reflects the potential of OS-1 to be used for other therapeutic applications in the future. The positive result surprised us, because we have not yet optimized our candidates by applying any medicinal chemistry. However, this will soon be performed once the mechanism of action is elucidated. On this subject, we have shown that OS-1 promotes a decrease of cellular senescence levels of cells and tissues by promoting apoptosis (decrease in phosphorylated Akt on Ser473), increasing DNA repair capacity (induction of BLM and SIRT6 gene expression) and preventing DNA-damage induced senescence (UVB exposure induction model).

What other areas of rejuvenation research do you think would benefit from a cosmetics approach, to speed adoption?

Most strategies targeting one of the hallmarks of aging could be useful for a cosmetic approach. The main limitation we see is the delivery of whatever rejuvenation technology through the stratum corneum, the outermost layer of the skin, which is very well designed to work as a barrier to protect the skin from potential harm or infections. Our peptide, as a reference, is considered small (10 amino acids) and we were fortunate to validate its ability to penetrate through the stratum corneum barrier and into the dermal layer. Larger molecules may face additional challenges in penetratration and to promote their effects in deeper skin layers.

Importantly, to be able to validate any technology to promote skin rejuvenation it is not a trivial process. Previous experience has shown that skin aging is a little bit different from aging in other tissues. Therefore, it will be important to validate other strategies while considering the important drivers for skin aging by testing on aged models that replicate chronological aging such as UV exposure, oxidative stress, and pollution, and not on less important drivers such as oncogene-induced and chemically-induced senescence. The ability to replicate these models required years of optimization and it is an ongoing process when you start considering not only the influence of age, but also how the diverse genetic background plays a significant role in this matter.

What is the future of OneSkin Technologies beyond your first senolytic product?

OneSkin's main goal is to build the first skincare line targeting cellular senescence and bring its own products to the market. We believe there is no proposal out there, focusing on skin, that tackles aging from its cause as we do. This makes us confident in the value our products will bring to consumers. After the first validation for aesthetic skin rejuvenation, we are going after other age-related skin disorders and eventually, age-related disorders beyond the skin. An oral application of our peptide is another avenue to be explored. As we intend to keep our focus mainly towards skin applications, we envision to explore these additional indications through partnerships with pharma or other longevity companies. Finally, OneSkin's main asset is our screening and validation platform, which will constantly screen and identify new leads, be them small molecules, peptides, natural compounds or combinations thereof, to target cellular senescence and senescence-associated diseases. We are determined to work to position our technologies in the forefront of the future therapies for aging and longevity.

Aging is characterized by a gradual and constant increase in health inequalities across socioeconomic groups, an association based on strong epidemiological evidence known as the social gradient in health. On average, individuals with lower socioeconomic position (SEP) have lower life expectancy, higher risk of age-related diseases, and poorer quality of life at older ages compared with less disadvantaged groups. Although lifestyles differ by SEP, unhealthy habits only partially explain this association.

The role of epigenetic mechanisms in response to trauma, and evidence for their involvement in intergenerational transmission of biological impacts of traumatic stress have been proposed to explain how social adversity gets biologically embedded, leading to differences in biological functionalities among individuals in different social conditions, especially at older ages. Epigenetics, specifically DNA methylation (DNAm) has been proposed as one of the most powerful biomarkers of biological aging and as one of the plausible biological mechanisms by which social adversities get 'under the skin' and affect physiological and cellular pathways leading to disease susceptibility.

Two measures of epigenetic clocks have gained considerable popularity, and the concept of epigenetic aging acceleration (EAA) has been introduced as the difference between predicted DNAm age and chronological age. EAA has been associated with all-cause mortality, cancer incidence and neurodegenerative disorders, as well as non-communicable disease risk factors such as obesity, poor physical activity, unhealthy diet, cumulative lifetime stress and infections.

Given the above, it can be assumed that the various epigenetic clocks describe different aspects of the biological (epigenetic) aging process. We previously showed a dose-response relationship between SEP and EAA. Further, our results suggest that the effect could be partially reversible by improving social conditions during life. In addition, ours and two more recent studies indicate that childhood SEP might have a stronger effect on EAA than adulthood SEP.

Despite extensive research in the field, to date no studies have compared the effect of SEP on epigenetic aging biomarkers with those of other lifestyle-related risk factors for age-related diseases. We aimed to systematically investigate the association of education level, as a proxy for SEP, with the total number of SEMs and 'accelerated aging' as assessed using the three epigenetic clocks, and to compare the independent effect of low education with those of the main modifiable risk factors for premature aging: smoking, obesity, alcohol intake, and physical inactivity, by conducting a meta-analysis including data for more than 16,000 individuals belonging to 18 cohort studies from 12 different countries worldwide.

Epigenetic aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect. Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.

Advanced glycation end products (AGEs) are non-enzymatic post-translational modifications of proteins derived from the condensation of reducing sugars and nucleophilic amino acid residues, such as lysine and arginine. Although AGEs are formed in the body as a part of normal metabolism, they can accumulate to high concentrations and contribute to the progressive decline of multiple organ systems. This process is accelerated in diabetics, owing to their hyperglycemic conditions. In addition to causing spontaneous damage by altering protein structure and function, AGEs also interact with the receptor for AGEs (RAGE), eliciting oxidative stress and activating the transcription factor NF-κB thought to be a major contributor of AGE-associated chronic inflammation and cellular damage.

Elevated levels of AGEs are linked to the pathology of many metabolic and degenerative diseases of aging, such as diabetic complications, atherosclerosis, and Alzheimer's disease. This association is manifested by age-dependent increases in cross-linking, browning, fluorescence, and AGE content in long-lived proteins such as collagens and lens crystallins. Structural characterization and synthesis of some of the more prevalent AGEs (e.g., glucosepane) have allowed more focused investigations into their individual chemical properties and formation. Indeed, chemical studies have shown strong correlations between specific AGEs and the development of age-related illnesses; however, it has been difficult to unequivocally demonstrate that any AGEs are direct causal factors largely due to the lack of tools for investigating the reversal of mature AGE modifications at the molecular level.

Here, we show that MnmC, an enzyme involved in a bacterial tRNA-modification pathway, is capable of reversing the AGEs carboxyethyl-lysine (CEL) and carboxymethyl-lysine (CML) back to their native lysine structure. Combining structural homology analysis, site-directed mutagenesis, and protein domain dissection studies, we generated a variant of MnmC with improved catalytic properties against CEL in free amino acid form. We show that this enzyme variant is also active on a CEL-modified peptidomimetic and an AGE-containing peptide that has been established as an authentic ligand of the receptor for AGEs (RAGE).

To the best of our knowledge, this is the first biochemical demonstration of an enzyme that can reverse a mature AGE-functionalized peptide. While the kinetic parameters, which are similar to known Amadoriases, could be substantially improved, C-MnmC variants represent lead catalysts for further directed evolution and development. As MnmC natively acts on nucleic acids, glycated DNA (e.g., carboxyethyl/carboxymethyl-deoxyguanosine) may also be suitable substrates to test in future studies. Such improved AGE-reversal tools could in principle enable a better understanding of the biology of AGEs at the molecular level, elucidate their direct roles in the pathogenesis of age-related diseases, and serve as leads for recombinant enzyme therapies.

The senescence-associated secretory phenotype (SASP) has recently emerged as both a driver of, and promising therapeutic target for, multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically monitored by a few dozen secreted proteins, has been greatly underappreciated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present 'SASP Atlas', a comprehensive proteomic database of soluble and exosome SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins, but also includes a subset of proteins elevated in all SASPs. Based on our analyses, we propose several candidate biomarkers of cellular senescence, including GDF15, STC1, and SERPINs. This resource will facilitate identification of proteins that drive specific senescence-associated phenotypes and catalog potential senescence biomarkers to assess the burden, originating stimulus and tissue of senescent cells in vivo.

Cellular senescence is a complex stress response that causes an essentially irreversible arrest of cell proliferation and development of a multi-component senescence-associated secretory phenotype (SASP). The SASP consists of myriad cytokines, chemokines, growth factors, and proteases that initiate inflammation, wound healing, and growth responses in nearby cells and tissues. In young and healthy tissues, the SASP is typically transient and tends to contribute to the preservation or restoration of tissue homeostasis. However, the increase in senescent cells with age and a chronic SASP are now known to be key drivers of many pathological hallmarks of aging, including chronic inflammation, tumorigenesis, impaired stem cell renewal, and others.

Using either or both of two transgenic mouse models that allow the selective elimination of senescent cells, or compounds that mimic the effect of these transgenes, data from several laboratories strongly support the idea that the presence of senescent cells drives multiple age-related phenotypes and pathologies, including age-related atherosclerosis, osteoarthritis, cancer metastasis and cardiac dysfunction, myeloid skewing in the bone marrow, kidney dysfunction, and overall decrements in healthspan.

Several types of stress elicit a senescence and secretory response, which in turn can drive multiple phenotypes and pathologies associated with aging in mammals. Some of these stressors have shared effects. For example, telomere attrition resulting from repeated cell division (replicative senescence), elevated reactive oxygen species, chromatin disruption, and even the activation of certain oncogenes all can cause genotoxic stress, as can a number of therapeutic drug treatments, such as anti-cancer chemotherapies and certain highly active antiretroviral therapies for HIV treatment or prevention. However, whether these stressors produce similar or distinct SASPs is at present poorly characterized. Therefore, a comprehensive characterization of SASP components is critical to understanding how senescent response can drive such diverse pathological phenotypes in vivo. It is also a critical step in clarifying how various stimuli, all acting through senescence, differentially affect health.

Excess weight is growing in frequency globally. Obesity is associated with morbidity and premature mortality and represents a major risk factor for many diseases especially cardiovascular disease. It is linked to a significant decrease in life expectancy of 5-10 years in comparison to persons with Body-Mass-Index (BMI) between 22.5 to 24.9. An elevated BMI, adipose tissue and muscular fat depositions, respectively, have been associated with aging. Aging is defined as deterioration of cellular and organ function with time related to many physiologic and phenotypical changes and represents the strongest risk factor for myocardial infarction, stroke, diabetes, and cancer. Therefore, premature aging-like syndromes such as Hutchinson-Gilford progeria syndrome (HGPS) are of particular interest in exploring pathophysiological changes of aging processes related to cardiovascular disease.

HGPS is based on mutations influencing the precise encoding and processing of lamin A (LMNA) an important filament protein in the nucleus of eukaryotic cells. LMNA is involved in the correct forming of a filamentous meshwork between chromatin and the nuclear membrane, keeping the nuclear envelope upright, which is essential to regulate processes like DNA replication, DNA repair, and RNA transcription. Individuals suffering from HGPS exhibit early cardiovascular atherosclerosis and often die due to heart attack and stroke as teenagers. Toward the end of life, HGPS patients also suffer from heart failure due to cardiac fibrosis and cardiomegaly.

In most HGPS cases, a single point mutation activates a cryptic splicing site causing the production of 50 amino acids truncated prelamin A called progerin. Progerin lacks the cleavage site for zinc-metalloproteinase (ZMPSTE24) resulting in accumulation in the nucleus, leading to disturbed lamina, telomere and DNA damages, apoptosis, early cellular senescence, and finally to deterioration of organ function. Astonishingly, it was shown that low amounts of progerin mRNA derived by alternative splicing are also expressed in healthy individuals leading to the discussion of the role of progerin in normal aging by various groups. Since obesity and premature aging are both accompanied with an increased cardiovascular morbidity and mortality, we aimed to investigate the association of BMI with respect to progerin mRNA expression in the blood of individuals with known cardiovascular disease.

This study shows that mRNA levels of the aging related lamin A splice variant progerin, associated with premature aging in HGPS, were significantly upregulated in subjects with BMI ≥ 25 kg/m2. Moreover, our data revealed a significantly positive correlation of BMI with progerin mRNA. These data provide to our knowledge for the first-time evidence for a possible involvement of progerin in previously observed accelerated aging of overweight and obese individuals potentially limiting their longevity. Our results also showed that progerin mRNA was positively correlated with C-reactive protein (CRP). This might suggest an association of progerin with an inflammatory response triggering accelerated aging. Moreover, we found an increase of the acute phase protein CRP in patients with BMI ≥ 25, indicating a higher systemic inflammatory status in the overweight group. This is consistent with prior findings where obesity was considered to predispose to local and systemic inflammation with ongoing activation of immune cells.

SIRT6 is often called the "longevity gene" because of its important role in organizing proteins and recruiting enzymes that repair broken DNA; additionally, mice without the gene age prematurely, while mice with extra copies live longer. The researchers hypothesized that if more efficient DNA repair is required for a longer lifespan, organisms with longer lifespans may have evolved more efficient DNA repair regulators. Is SIRT6 activity therefore enhanced in longer-lived species?

To test this theory, the researchers analyzed DNA repair in 18 rodent species with lifespans ranging from 3 years (mice) to 32 years (naked mole rats and beavers). They found that the rodents with longer lifespans also experience more efficient DNA repair because the products of their SIRT6 genes - the SIRT6 proteins - are more potent. That is, SIRT6 is not the same in every species. Instead, the gene has co-evolved with longevity, becoming more efficient so that species with a stronger SIRT6 live longer.

The researchers then analyzed the molecular differences between the weaker SIRT6 protein found in mice versus the stronger SIRT6 found in beavers. They identified five amino acids responsible for making the stronger SIRT6 protein more active in repairing DNA and better at enzyme functions. When the researchers inserted beaver and mouse SIRT6 into human cells, the beaver SIRT6 better reduced stress-induced DNA damage compared to when researchers inserted the mouse SIRT6. The beaver SIRT6 also better increased the lifespan of fruit flies versus fruit flies with mouse SIRT6. Next steps in the research involve analyzing whether species that have longer lifespans than humans - like the bowhead whale, which can live more than 200 years - have evolved even more robust SIRT6 genes.

Tissue engineering strategies to replace or supplement the extracellular matrix that degrades following a heart attack are not new, but most promising hydrogels cannot be delivered to the heart using minimally invasive catheter delivery because they clog the tube. Researchers have now demonstrated a novel way to deliver a bioactivated, biodegradable, regenerative substance through a noninvasive catheter without clogging.

When a person has a heart attack, the extracellular matrix is stripped away and scar tissue forms in its place, decreasing the heart's functionality. Because of this, most heart attack survivors have some degree of heart disease, the leading cause of death in America. "We sought to create a peptide-based approach because the compounds form nanofibers that look and mechanically act very similar to native extracellular matrix. The compounds also are biodegradable and biocompatible. Most preclinical strategies have relied on direct injections into the heart, but because this is not a feasible option for humans, we sought to develop a platform that could be delivered via intracoronary or transendocardial catheter."

Peptides are short chains of amino acids instrumental for healing. The team's approach relies on a catheter to deliver self-assembling peptides - and eventually a therapeutic - to the heart following myocardial infarction, or heart attack. The team's preclinical research was conducted in rats and segmented into two proof-of-concept tests. The first test established that the material could be fed through a catheter without clogging and without interacting with human blood. The second determined whether the self-assembling peptides could find their way to the damaged tissue, bypassing healthy heart tissue. Researchers created and attached a fluorescent tag to the self-assembling peptides and then imaged the heart to see where the peptides eventually settled. "In previous work with responsive nanoparticles, we produced speckled fluorescence in the heart attack region, but in this case, we were able to see large continuous hydrogel assemblies throughout the tissue."

Since low-density lipoprotein, or LDL, cholesterol entry into the artery wall drives the development of atherosclerosis, or hardening of the arteries, and atherosclerosis leads to heart attacks and strokes, future treatments preventing the process may help decrease the occurrence of these life-threatening conditions. A new study reveals for the first time how a protein called SR-B1 (short for scavenger receptor class B, type 1) ferries LDL particles into and then across the endothelial cells that line arteries. The study also found that a second protein called dedicator of cytokinesis 4, or DOCK4, partners with SR-B1 and is necessary for the process.

In the early stages of atherosclerosis, LDL that has entered the artery wall attracts and is engulfed by important immune system cells called macrophages that ingest, or "eat," LDL particles. LDL-laden macrophages become foam cells that promote inflammation and further the development of atherosclerotic plaques. The plaques narrow the artery and can become unstable. Plaques that rupture can activate blood clotting and block blood flow to the brain or heart, resulting in a stroke or heart attack. In studies of mice with elevated cholesterol, the investigators determined that deleting SR-B1 from the endothelial cells lining blood vessels resulted in far less LDL entering the artery wall, fewer foam cells formed, and atherosclerotic plaques that were considerably smaller.

In their studies, the researchers compared SR-B1 and DOCK4 abundance in areas of the mouse aorta that are prone to plaque formation compared with regions less likely to become atherosclerotic. They found higher levels of SR-B1 and DOCK4 in the disease-prone regions long before atherosclerotic plaques formed. This finding suggests that atherosclerotic lesions may be more common in particular artery sites because of more SR-B1 and DOCK4 present there. To determine if these findings might apply to people, the researchers reviewed data on atherosclerotic and normal arteries from humans in three independent databases maintained by the National Institutes of Health (NIH). In all three databases, SR-B1 and DOCK4 were more abundant in atherosclerotic arteries compared with normal arteries. The researchers are now exploring the possibility of using gene therapy to turn off or reduce the function of SR-B1 or DOCK4 in the endothelial cells that line arteries in order to prevent atherosclerosis.

In 2007, researchers already knew that exercise reduces the risk of cardiovascular disease as much as cholesterol-lowering statin drugs do. By analyzing biomarkers in the blood of 27,055 women participating in a long-term study, and other objective measures, they hoped to tease out how much of the benefit was attributable to improved blood pressure, to lower body weight, or to something else. "We were actually surprised that reduced inflammation was the biggest explainer, the biggest contributor to the benefit of activity, because we hadn't hypothesized that. We knew that regular exercise does reduce inflammation over the long term, but we also knew that acute exercise transiently increases inflammatory biomarkers during and immediately after exertion." About a third of the benefit of regular exercise, they found, is attributable to reduced inflammation. The anti-inflammatory effect of exercise was much greater than most people had expected. That raised another question: whether inflammation might also play a dominant role in other lifestyle illnesses that have been linked to cardiovascular disease, such as diabetes and dementia.

In 2017, two cardiologists, who suspected such a link, published the results of a human clinical trial which involved more than 10,000 patients in 39 countries, and was primarily designed to determine whether an anti-inflammatory drug, by itself, could lower rates of cardiovascular disease in a large population, without simultaneously lowering levels of cholesterol, as statin drugs do. The answer was yes. But the researchers went a step further, building into the trial additional tests seeking to clarify what effect the same anti-inflammatory drug, canakinumab, might have on illnesses seemingly unrelated to cardiovascular disease: arthritis, gout, and cancer. Only the researchers themselves, and their scientific colleagues, were unsurprised by the outcome. Lung cancer mortality dropped by as much as 77 percent. Reports of arthritis and gout also fell significantly.

In medicine, believing something is true is not the same as being able to prove it. Because the idea that inflammation - constant, low-level, immune-system activation - could be at the root of many noncommunicable diseases is a startling claim, it requires extraordinary proof. Can seemingly unconnected illnesses of the brain, the vasculature, lungs, liver, and joints really share a deep biological link? Evidence has been mounting that these common chronic conditions - including Alzheimer's, cancer, arthritis, asthma, gout, psoriasis, anemia, Parkinson's disease, multiple sclerosis, diabetes, and depression among them - are indeed triggered by low-grade, long-term inflammation. But it took that large-scale human clinical trial to dispel any lingering doubt: the immune system's inflammatory response is killing people by degrees.

Now the pertinent question is why, and what can be done about it. The pharmaceutical industry is deeply interested in finding ways to stop inflammation with medicines like canakinumab, an orphan drug that blocks a specific pro-inflammatory pathway called IL-1beta. But some researchers suggest that the inflammatory process - a normal and necessary part of the natural immune response - has itself has been misunderstood. Scientists know that the process can be turned on and off, but have only recently understood that this doesn't mean normal physiology will resume once the inflammation caused by infection, injury, or irritant has been shut down. Instead, the restoration of health is an active phase of the inflammatory process itself, facilitated by a little-known class of molecules called pro-resolving mediators - the protectins, resolvins, maresins, and lipoxins - brimming with marvelous, untapped, regenerative capacities.

By injecting cells that support blood vessel growth into muscles depleted by inactivity, researchers say they are able to help restore muscle mass lost as a result of immobility. The research, conducted in adult mice, involved injections of cells called pericytes, which are known to promote blood vessel growth and dilation in tissues throughout the body. The injections occurred at the end of a two-week period during which the mice were prevented from contracting the muscles in one of their hind legs. "Just as the mice were becoming mobile again, we transplanted the pericytes and we found that there was full recovery of both muscle mass and the vasculature, too."

The team also observed that muscle immobility itself led to a significant decline in the abundance of pericytes in the affected muscle tissues. "We know that if you are under a condition of disuse - for example, as a result of long-term bed rest, or the immobilization of a body part in a cast - you lose muscle mass. And even when you come out of that state of immobility and you start moving your muscles again, there's this really long, slow process of recovery. Older adults might never fully rebuild the lost muscle mass after a period of immobility. They can't recover, they become disabled, and there's this downward spiral. They may become institutionalized and experience early mortality. To my knowledge, no one has demonstrated that anything has been effective in improving the recovery process. We're excited by the new findings because we hope to one day use these cells or biomaterials derived from these cells to help restore lost muscle mass."

How quickly do we experience the benefits of exercise? A new study of healthy older adults shows that just one session of exercise increased activation in the brain circuits associated with memory - including the hippocampus - which shrinks with age and is the brain region attacked first in Alzheimer's disease. "While it has been shown that regular exercise can increase the volume of the hippocampus, our study provides new information that acute exercise has the ability to impact this important brain region."

The research team measured the brain activity (using fMRI) of healthy participants ages 55-85 who were asked to perform a memory task that involves identifying famous names and non famous ones. The action of remembering famous names activates a neural network related to semantic memory, which is known to deteriorate over time with memory loss.

This test was conducted 30 minutes after a session of moderately intense exercise (70% of max effort) on an exercise bike and on a separate day after a period of rest. Participants' brain activation while correctly remembering names was significantly greater in four brain cortical regions (including the middle frontal gyrus, inferior temporal gryus, middle temporal gyrus, and fusiform gyrus) after exercise compared to after rest. The increased activation of the hippocampus was also seen on both sides of the brain. "Just like a muscle adapts to repeated use, single sessions of exercise may flex cognitive neural networks in ways that promote adaptations over time and lend to increased network integrity and function and allow more efficient access to memories."

Not only have there been more than 200 failed trials for Alzheimer's, it's been clear for some time that researchers are likely decades away from being able to treat this dreaded disease. Which leads me to a prediction: There will be no effective therapy for Alzheimer's disease in my lifetime. Alzheimer's sits right at the confluence of a number unfortunate circumstances. If you understand why there won't be much headway on Alzheimer's, you'll also understand a bit more why modern medicine has been having fewer breakthroughs on major diseases.

For decades it was widely believed that the cause of Alzheimer's was the build-up of abnormal proteins called amyloid and tau. These theories dominated the field and led some to believe we were on the verge of effective treatments - through preventing or removing these abnormal proteins. But had the theories been correct we would likely have had at least one or two positive clinical trials. In retrospect, the multi-decade amyloid fixation looks like a mistake that could have been avoided. It was always possible that the classic plaques and tangles were epiphenomena of aging and not the cause of the disease. Epiphenomena are characteristics that are associated with the disease but are not its cause.

But even more convincing that researchers are closer to the beginning than the end in understanding the cause of Alzheimer's is the long list of alternative theories. This now includes but is not limited to: infection, disordered inflammation, abnormal diabetes-like metabolism, and numerous environmental toxins. And the past few years have seen more evidence for viral, bacterial, and fungal infections. These viral and bacterial hypotheses were portrayed as eureka moments. But this begs the question: How did powerful tools of epidemiology miss associations with things like cold sores and gum disease?

Here's the thing - regardless of type, Alzheimer's has a powerful age-related association. This is true even for patients with early-onset inherited form of Alzheimer's. Give someone the worst possible genome for Alzheimer's - including the dreaded APOE e4 gene that may be associated with a 10-fold increase in risk - and that person still needs to age a bit before developing the disease. If correct, this conception of the disease means we're even further away from an effective treatment. Aging is not disease. It is the normal arc of life and an ineluctable part of being human ("dust unto dust"). As such, the biology of aging didn't get the attention that was bestowed on organ systems and diseases during the golden years of research funding. In retrospect, I think this may have been a grave mistake. If you list the risk factors for the major diseases of modern life - heart disease, diabetes, dementia - the most powerful is almost always age. Bottom line: We also lack an understanding of the basic science of Alzheimer's most important risk factor.

Chronic inflammation is believed to contribute to the pathogenesis of many age-related diseases including cardiovascular disease. Chronic inflammation, particularly from activation of innate immunity, is highly sensitive to changes in the tissue environment that is associated with aging. The immune cell type that is particularly influenced by changes in its microenvironment is the monocyte/macrophage. These cells display a high level of plasticity and heterogeneity in response to their environmental cues. For example, based on the response of cultured macrophages to treatment with IL-4 or interferon γ, cells have been proposed to polarize to either M2 or M1 phenotypes, respectively. Although the M1-M2 polarization concept is useful in describing the two extremes of macrophage phenotypes, the concept does not accurately recapitulate the complex response of cells to their driving tissue microenvironment in vivo.

The plasticity of monocytes/macrophages are determined by the constellation of transcription factors that are activated and expressed in response to environmental cues. To understand the role of GATA3 transcription factor in the pathogenesis of cardiac diseases, we generated myeloid-specific GATA3 knockout mice and found that their cardiac function is significantly improved in response to ischemia or pressure overload compared with the GATA3 sufficient control group. Analysis of the profile of monocytes/macrophages in vivo revealed that GATA3-positive macrophages are not found in the healthy adult tissue. In the setting of a myocardial infarction, however, the deficiency of GATA3-positive macrophages led to a significant improvement of cardiac function compared with the GATA3 sufficient control group.

This improvement was found to be associated with the presence of many pro-inflammatory macrophages, but, few "anti-inflammatory/reparative" macrophages. This was unexpected because the prevailing hypothesis is that controlling the pro-inflammatory pathways may improve cardiac function. Our data suggest that exuberant repair, rather than unrestrained inflammation, may contribute to the excessive and maladaptive remodeling of the myocardium in the post myocardial infarction setting. Extensive evidence suggests that the aging heart undergoes fibrotic remodeling. Although targeting of pro-inflammatory pathways is thought to be an important strategy to control excessive tissue fibrosis, numerous anti-inflammatory drugs have been found to have little or no therapeutic benefit in fibrotic diseases. Our data suggest that GATA3-positive macrophages, which presumably display an M2 phenotype, are highly fibrogenic. It is therefore possible that targeting a subset of inflammatory cells, rather than global inflammation, may be a useful therapeutic strategy to control fibrotic diseases associated with aging.

Age-associated chronic inflammation is characterized by unresolved and uncontrolled inflammation with multivariable low-grade, chronic and systemic responses that exacerbate the aging process and age-related chronic diseases. Currently, there are two major hypotheses related to the involvement of chronic inflammation in the aging process: molecular inflammation of aging and inflammaging. However, neither of these hypotheses satisfactorily addresses age-related chronic inflammation, considering the recent advances that have been made in inflammation research. A more comprehensive view of age-related inflammation, that has a scope beyond the conventional view, is therefore required.

Based on the available findings from biochemical, molecular, and systems analyses, we propose the senoinflammation concept. It provides not only a broader scope, but also creates an intricate network among many inflammatory mediators that can lead to systemic chronic inflammation. When gene regulation is impaired because of constant damage to the genomic DNA by augmented oxidative susceptibility during the aging progresses, several key inflammatory transcription factors, including p53, AP-1, STAT, and NF-κB, that are important in cell survival become over-activated.

The resulting aberrant gene regulation in senescent cells leads them into a proinflammatory state, thereby altering systemic chemokine or cytokine activities. The proinflammatory senescent cell secretome imposes further stresses on the intracellular organelles, as well as tissues, organs, and systems, thus influencing metabolic disorders such as insulin resistance. It seems plausible that a vicious cycle takes place between senescent cell secretome induction and metabolic dysregulation, as proposed in the senoinflammation concept, and this may well be the underpinning of the aging process and age-associated diseases.

It is hoped that a better understanding of the molecular mechanisms involved in senoinflammation will provide a basic platform for the identification of potential targets that can suppress age-related chronic inflammation and thereby lead to the development of effective interventions to delay aging and suppress age-associated diseases.

Aging is a predisposing factor for cardiac and pulmonary fibrosis, with the prevalence of heart failure and fibrotic respiratory diseases such as idiopathic pulmonary fibrosis (IPF) increasing dramatically with advancing age. The aging of cardiac and lung tissue ultimately results in structural remodeling of the extracellular matrix (ECM) caused by alterations in the concentration and organization of ECM components such as collagen and elastin. Biological aging is accelerated by the cumulative damage and stress that occurs during a lifetime. This premature aging is particularly pertinent to the pulmonary system, which is subjected to lifelong challenges by airborne pollutants, particulates, and pathogens. Similarly, due to the high metabolic demand of the heart, large mitochondrial population and infrequent cardiomyocyte turnover, the heart is also highly susceptible to cumulative oxidative damage and stress with age. Cellular and immunological changes occur concomitantly with age-related tissue remodeling.

There are a great many hallmarks that represent common denominators of aging, such as stem cell exhaustion, genomic instability, telomere attrition, epigenetic alteration, and loss of proteostasis; in this review we focus on four processes of aging which play an integral role in fibrosis. Senescence, inflammaging, compromised autophagy and mitochondrial dysfunction are interrelated processes, which reduce the regenerative capacity of the aged heart and lung, and have been shown to be involved in cardiac fibrosis and IPF. As a consequence, challenges to an aging heart or lung are more likely to lead to pathological tissue remodeling rather than wound resolution and tissue restitution. This is exemplified in experimental models that show cardiac fibrosis in mice post-myocardial infarction increases with age. Similarly, pulmonary fibrosis in experimental lung injury is exacerbated by aging.

Age-related processes such as senescence and inflammaging diminish the regenerative capacity of damaged cardiac and pulmonary tissue, increasing the likelihood of pathological fibrosis following injury or challenge. What is interesting about these two processes is that at low levels, they mediate beneficial effects, but as you age and the level increases, they become deleterious. This is most evident with senescence, which protects the organism from cancer but which, in excess, can promote aging and the hallmark features of fibrosis. Furthermore, inflammaging and its sustained increase of inflammatory markers, which at normal levels regulate the immune response, contributes to the acquired resistance of myofibroblasts to apoptosis, and the low grade chronic inflammation which sustains the persistent fibrosis of cardiovascular disease and IPF. Given the similarities between cardiac and pulmonary fibrosis, investigating targets and testing future treatments in both organs with a focus on these key age-related processes seems justifiable and may lead to better treatment opportunities.