Fight Aging! Newsletter, February 22nd 2021

UNITY Biotechnology, Inc., a biotechnology company developing therapeutics to slow, halt, or reverse diseases of aging, today announced new preclinical research that reveals a novel mechanism for treating age-related eye diseases - such as diabetic retinopathy and diabetic macular edema - by restoring vascular health in the retina. By selectively eliminating the senescent cells accumulating in diseased blood vessels of the eye, researchers identified a way to target diseased vasculature while leaving healthy blood vessels intact, thus enabling the retina to repair itself.

Researchers demonstrated that diseased blood vessels in the retina trigger molecular pathways associated with aging, collectively termed cellular senescence. The authors used a combination of animal models and human samples to identify a molecular target, called Bcl-xL, that is highly expressed in diseased retinal blood vessels. Targeting these senescent cells with a single dose of UNITY's Bcl-xL small molecule inhibitor led to selective elimination of diseased vasculature, while enabling functional, healthy blood vessels to reorganize and regenerate.

Attenuating pathological angiogenesis in diseases characterized by neovascularization such as diabetic retinopathy has transformed standards of care. Yet little is known about the molecular signatures discriminating physiological blood vessels from their diseased counterparts, leading to off-target effects of therapy. We demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cellular senescence. Senescent (p16 INK4A-expressing) cells accumulate in retinas of patients with diabetic retinopathy and during peak destructive neovascularization in a mouse model of retinopathy.

Using either genetic approaches that clear p16 INK4A-expressing cells or small molecule inhibitors of the anti-apoptotic protein BCL-xL, we show that senolysis suppresses pathological angiogenesis. Single-cell analysis revealed that subsets of endothelial cells with senescence signatures and expressing Col1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conducive to physiological vascular repair. These findings provide mechanistic evidence supporting the development of BCL-xL inhibitors as potential treatments for neovascular retinal disease.

Reduced capillary density with aging is attributed to diminished levels of angiogenic growth factors (such as VEGF), an imbalance between production of angiogenic and anti-angiogenic growth factors, and reduction of nitric oxide release and impaired vasodilation. The Neuroangiogenesis Hypothesis has been proposed, wherein a decline in growth factors and angiogenic cytokines leads to a reduction in vessel density and cognition. Restoration of vessel density through administration of growth factors, such as VEGF, is proposed as a treatment to prevent development of Alzheimer's disease (AD) symptoms. In addition to vessel loss, aging is linked to increased capillary tortuosity and a thickened basement membrane. Pericytes are lost or become dysfunctional, causing blood-brain barrier dysfunction and impaired flow regulation that decreases oxygen concentration in tissue.

Vascular risk factors are prominent in aged populations. This may be due to aging-induced inflammation and cytokine release, leading to endothelial dysfunction and arterial stiffening. Hypertension is associated with microvascular abnormalities such as endothelial swelling and reduced capillary density. This microvascular deficiency in hypertension is potentially aggravated by a deficiency in circulating insulin-like growth factor 1 (IGF-1) due to aging.

The reduced vessel density at older ages might be attributable to the aging process and reduced expression of angiogenic growth factors. In brains without AD, decline in growth factors with aging, such as VEGF, fibroblast growth factor (FGF-1 and FGF-2), and angiopoietin, yield slow recovery in tissue wound injuries due to reduced angiogenic capabilities, or display reduced angiogenesis in response to hypoxia. In a human study, researchers found significant reduction in serum VEGF relative to both amnestic mild cognitive impairment and control (healthy) individuals. Transforming growth factor β1 (TGF-β1) (an angiogenic growth factor) serum concentration was reduced in AD, with the reduction in VEGF and TGF-β1 levels correlating with cognitive impairment severity. It was hypothesized that this indicates reduction in angiogenic growth factors contribute to cognitive impairment.

Due to reduced capillary density with aging, researchers proposed VEGF and growth factor administration for restoring capillary density and blood flow. A study in TgCRND8 AD mice overexpressing VEGF found partial recovery of vessel density and restoration of memory impairments, supporting enhancing vascular growth as a method for improving cognition. There are factors to consider in applying this therapy to humans. VEGF in high concentrations may induce blood-brain barrier leakage. Many newly formed vessels during angiogenesis are leaky with abnormal morphology.

Regrowth of vascular is more than increasing vessel number through administering VEGF. Newly formed vessels adjust their diameters, potentially differentiate into arteries or veins, and recruit support cells such as smooth muscle cells, pericytes, and fibroblasts to produce a functional vessel network. Expanding growth factor therapy to AD will require consideration of relative concentrations of naturally occurring growth factors unique to each subject and state of dementia, delivery method, and determining growth factors to administer.

A related therapy to growth factor administration that overcomes some deficiencies is exercise. Exercise increases concentration of a variety of angiogenic molecules such as Ang1 and Ang2, VEGF, fibroblast growth factor (FGF, upregulates VEGF, and induces vasodilation through nitric oxide), transforming growth factor (TGF, regulates extracellular matrix formation), and platelet derived growth factor (PDGF, mitogen for smooth muscle cells, fibroblasts, and glia cells). Mice provided access to running wheels demonstrated elevated brain microvascular efficiency and increased blood flow in the hippocampus.

Centenarians, the most aged individuals, should accumulate senescent cells and suffer from their deleterious effects, however, they enjoy a compression of morbidity. We have shown that they overexpress B-cell lymphoma-extra large (Bcl-xL). Bcl-xL could avoid an excessive burden of senescent cells through the regulation of intrinsic apoptosis, mitochondrial bioenergetics and oxidative stress. On the other hand, Bcl-xL maintains a fully functional immune system that ensures an efficient clearance of senescent cells. Moreover, there is a paradox, as inhibitors of Bcl-xL have been employed as senolytic agents, which have been shown to protect from aging in animal models.

Despite its well-documented anti-apoptotic role, Bcl-xL is also related to mitochondrial bioenergetics by modulating mitochondrial fusion and fission, increasing total mitochondrial biomass, and enhancing the efficiency of the ATP synthesis. As cellular senescence can be both beneficial and detrimental for the organism, accordingly, Bcl-xL might play a dual role on senescence.

A possible hypothesis could be that during acute senescence, Bcl-xL effects on mitochondria would help senescent cells to cover their metabolic demand to secrete the SASP to promote their clearance as part of the senescence-clearance-regeneration procedure. However, senescent cells are also characterized by dysfunctional mitochondria, due to an imbalance between mitochondrial fission and fusion, which is critical for the functionality of the mitochondrial network. In this scenario, Bcl-xL might avoid the accumulation of dysfunctional mitochondria in senescent cells, thus preventing their detrimental effect on tissue homeostasis.

Senescent cells mainly depend on the immune system to be cleared; thus, a dysfunctional immune system will lead to accumulation of senescent cells within tissues. To promote the depletion of senescent cells, senolytic drugs aim to eliminate senescent cells without affecting quiescent or proliferating cells. Since the expression of anti-apoptotic and pro-apoptotic genes is higher in senescent cells compared to healthy cells, inhibitors of Bcl-xL have been described as senolytic agents because they only induce apoptosis in senescent cells, both in vitro and in vivo. ABT737, ABT263 or Navitoclax, which targets the Bcl-2/Bcl-xL proteins, is a potent senolytic drug that selectively kills senescent cells, regardless of how they were induced.

Inasmuch as one enjoys being alive, waiting longer until the signs of frailty and old age occur seems an appealing proposition, and so there is an entire field of research dedicated to understand the aging process. A recent summary for a popular audience is in David Sinclair's recent book Lifespan. But I wanted to provide a deeper and more concise explanation, plus communicating not only the results but also their robustness. There is also a previous Longevity FAQ from Laura Deming, but I thought something a bit longer that explains the field from the ground up should exist.

At first, reading about research regarding longevity can seem like magic: "We knocked out Sirt1 in mice, leading to reduced lifespan". That sentence is not only compressing a lot of information (What does it mean to knock out? What's Sirt1?) but also once we know that knocking out Sirt1 means to stop a gene from being expressed (i.e. stopping the cell from manufacturing the protein associated with that gene), we may want to know things like "Are there different ways of knocking out genes? How do different genes related in the genetics of aging relate to each other? If we do the same things in dogs, does it work?"

My goal here is to demystify what seems initially obscure, and to make available a summary of the current state of the art, the quality of the evidence available so far, and what promising avenues of research are being pursued at the moment.

Longevity research is an exciting area that has been making great progress in recent years. From the early discoveries that ageing can be modulated to the current advances in understanding how aging works, and how therapies could be developed to live longer, healthier lives. Progress seems easier on the "healthier" side of things, with many of studies showing that it is easier to prolong healthspan or expected lifespan and cure certain conditions that occur in the old age rather than the maximum lifespan of our species. Current research seems like it could enable most people to live past 100 years in reasonably healthy conditions, a feat that, to a lesser degree, is accomplished today by a tiny fraction of supercentenarians.

This article reviews some key strands of demographic research on past trends in human longevity and explores possible future trends in life expectancy at birth. Demographic data on age-specific mortality are used to estimate life expectancy, and validated data on exceptional life spans are used to study the maximum length of life. In the countries doing best each year, life expectancy started to increase around 1840 at a pace of almost 2.5 years per decade. This trend has continued until the present. Contrary to classical evolutionary theories of senescence and contrary to the predictions of many experts, the frontier of survival is advancing to higher ages. Furthermore, individual life spans are becoming more equal, reducing inequalities, with octogenarians and nonagenarians accounting for most deaths in countries with the highest life expectancy.

If the current pace of progress in life expectancy continues, most children born this millennium will celebrate their 100th birthday. Considerable uncertainty, however, clouds forecasts: Life expectancy and maximum life span might increase very little if at all, or longevity might rise much faster than in the past. Substantial progress has been made over the past three decades in deepening understanding of how long humans have lived and how long they might live. The social, economic, health, cultural, and political consequences of further increases in longevity are so significant that the development of more powerful methods of forecasting is a priority.

Since the first reported cases with severe acute respiratory syndrome caused by a novel coronavirus (SARS-CoV2), this disease called coronavirus disease (COVID-19) has expanded worldwide being considered by World Health Organization as a pandemic. Although this virus may infect people regardless of age, race or sex, older subjects have been identified as a high-risk group regarding the clinical outcome of the disease, both for developing severe pneumonia with respiratory distress and death. Although global mortality rate directly related to SARS-CoV2 infection is unknown (a real infectious rate is not well known), mortality rate among severely elderly patients (between 60-90 years old) is around 50%, even in countries with significant lower deaths. Hence, apart from other risk factors linked to a poor clinical outcome, such as hypertension, diabetes, cardiovascular disease, cancer, or chronic lung disease, old age itself can be also considered as an independent risk factor associated with SARS-CoV2-related severe pneumonia and death.

From an immunopathogenic viewpoint, COVID-19 disease has probably a multifactorial nature and the final severe lung damage observed in COVID-19 could be caused by an uncontrolled proinflammatory cytokine cascade (called "cytokine storm"), driven mainly by interleukin-6 (IL-6) and other proinflammatory cytokines such as IL1β, IL8, CXCL10, and CCL2. Based on this hypothesis, apart from non-specific antiviral agents, anti-inflamatory drugs have been proposed to be used in patients with advanced COVID-19 disease. However, which immunopathogenic status precedes this "cytokine storm" and why the elderly population is more severely affected, are currently unanswered questions. Thus, we propose that immunosenescence and age-related thymic dysfunction could play a relevant role in current COVID-19 disease scenario.

According to our dual physiopathological hypothesis, in addition to impaired thymic function, we believe that elderly subjects at baseline show a systemic low-level chronic inflammation. Their population of monocytes generate a great amount and variety of cytokines (multiple circulating cytokines). These cells of elderly subjects, when stimulated by pathogen-associated molecular patterns receptors like TLR by a novel agonist (SARS-CoV2 antigen), could generate the massive and polyfunctional proinflammatory cytokine release that characterized COVID-19, and that would trigger the respiratory distress and multiorgan failure as clinical outcome.

Hypertension is a leading risk factor for cardiovascular, cerebrovascular, and many other diseases. Vascular remodeling results from blood pressure elevation, and progressively becomes a crucial cause of hypertension. However, during vascular remodeling no symptoms except occasional blood pressure elevation are observed. Neither attention nor treatment would be considered until the diagnosis of hypertension is established. Thus, timely therapy is urgent for the prevention and treatment of early-stage vascular remodeling.

Vascular remodeling results initially from passive physiological adaptation to blood pressure changes, then progresses into an active pathological process caused by elevated blood pressure, aging, and several other factors. An earlier study showed the critical role of inflammation in the pathological changes involved in vascular remodeling. Emerging evidence indicates that infiltrating proinflammatory cells are essential for the migration and infiltration of inflammatory factors. Several inflammatory factors were shown to affect blood pressure and vascular function leading to vascular remodeling and dysfunction. Thus, it is reasonable to hypothesize that by regulating inflammatory cells and their environment might aid in the treatment and prevention of vascular remodeling and hypertension-related vascular diseases.

Limb remote ischemic conditioning (LRIC) is a physiological treatment that protects against acute ischemic events and traumatic injury. Chronic remote ischemic conditioning simulates regular exercise and exerts its protective effect via humoral and immunological regulation. Some clinical cases reported that LRIC could decrease blood pressure. However, studies on whether LRIC positively affects chronic vascular remodeling and blood pressure are scant. Considering all the available evidence, we hypothesize that LRIC would exert a protective effect on hypertension-related vascular remodeling, thus delaying vascular stiffness and aging caused by structural remodeling.

In this study, LRIC of rats was performed once a day for 6-weeks. Blood pressure, vascular remodeling, and inflammation were compared among normotensive Wistar-Kyoto rats (WKY), WKY RIC group, spontaneously hypertensive rat (SHR) control group, and SHR RIC. LRIC treatment decreased blood pressure in SHR. LRIC ameliorated vascular remodeling by decreasing cross-sectional area, suppressing deposition of the extracellular matrix, and hypertrophy of smooth muscle cell in conduit artery and small resistance artery. LRIC decreased proinflammatory factors while increasing the anti-inflammatory factors in the circulation. LRIC decreased circulating monocyte and natural killer T-cell levels.

Long-term LRCI treatment (twice a day for 4-weeks) was performed on patients with prehypertension or early-stage hypertension. Blood pressure and pulse wave velocity (PWV) were analyzed before and after LRIC treatment. LRIC treatment decreased blood pressure and improved vascular stiffness in patients. In conclusion, long term LRIC could decrease blood pressure and ameliorate vascular remodeling via inflammation regulation.

Inflammation is supposed to help protect us - it's part of an immune response to fight off pathogens and clear infections. But patients with cardiac disease often have chronic inflammation that damages their hearts, even with no infection present. When a heart attack or other issue damages the heart and leaves it unable to pump enough blood to meet the body's needs, the heart tries to compensate by pumping faster. The cardiac muscle cells have to work harder and this stress causes them to release molecules known as reactive oxygen species. Looking at the hearts of mice, the researchers determined that products of these reactive oxygen species modify proteins in the heart so that the immune system views them as a potential threat.

"The formation of these new targets is what we found that our T cells are robustly responding to. And this ultimately leads to inflammation that affects the heart." The researchers confirmed that these modified proteins also appeared in the cardiac tissue of human patients whose hearts were failing. Chronic inflammation can cause structural changes to the heart - the muscle can become enlarged or develop fibrous tissue, impeding its ability to pump blood efficiently and leading to further deterioration. But anti-inflammatory treatments or attempts to broadly target reactive oxygen species have yet to be successful. They often end up interfering with other aspects of the immune system or necessary physiological processes.

With this improved understanding of how T cells are being activated in patients with heart disease, the researchers hope to develop more targeted treatments. They have already tested one possibility in mice: an agent that binds to the specific molecules altering cardiac proteins.

Cambrian Biopharma, a distributed drug discovery company, exited stealth today with the announcement that it has raised 60 million in private financing to develop medicines to extend healthy lifespan. By working like a hub-and-spoke model to develop a family of companies, Cambrian hopes to promote a thriving environment, building expert teams in drug discovery, development, clinical trials, finance, and market analysis as a shared resource for each pipeline company to use.

"I think that there's a lot of opportunity in this space and one of the things that we really need is companies that can move fast with a lot of capital. Hallmarks of aging, as well as other types of molecular damage that accumulate in our bodies as we get older, are in scope for Cambrian, we are really building an R&D company first, one that's making allocation decisions, not investments across a series of our pipeline companies."

This longevity platform approach is very much like Juvenescence and Life Biosciences and is another welcome demonstration of longevity investment category growth. Cambrian scientists are targeting the nine hallmarks of aging, including cellular senescence, sustained tissue inflammation, and mitochondrial dysfunction. They are leveraging breakthroughs in fields that include immunology, genomics, and epigenetics, and technologies that range from gene editing to new stem cell therapies.

Cambrian has put three major categories of aging at the top of its to-do list; it plans to tackle intracellular dysfunction (things that go wrong inside cells, such as mutating DNA or shrinking telomeres), cellular dysfunction (whole-cell level problems, such as senescence or energy pathway break down) and tissue level dysfunction (stem cells exhaustion, chronic inflammation, or the breakdown of tissue architecture). To date, Cambrian has 14 novel therapies under development within its stable of companies. The first of these to be disclosed is Sensei Bio, which has as its lead therapeutic product candidate a genetically engineered bacteriophage vaccine that has already demonstrated promising data in a Phase 1/2 human clinical trial of patients with late-stage head and neck cancer.

A new study which examined the population of Denmark has found that people age 70 and older are having fewer strokes, and fewer people of all ages are dying from the disease. In older people, researchers found declines in both ischemic stroke, caused by a blockage of blood flow to the brain, and intracerebral hemorrhage, when a blood vessel bursts inside the brain. "Stroke is a leading cause of death and disability in the world. Recent research on the incidence of stroke has been mixed, and some studies have reported an increase among young people. However, our research found no increase in stroke among young people, and it also found the incidence of stroke declining among older people, which is encouraging."

For the study, researchers used national health care registries in Denmark to identify all people in the country hospitalized with a first-time stroke between 2005 and 2018. They identified 8,680 younger adults age 18 to 49 who had a stroke during that time, and 105,240 older adults age 50 and older. Researchers calculated yearly incidence rates for both ischemic and hemorrhagic stroke based on the Danish population. They also calculated incidence rates based on age.

Researchers found the incidence rate of stroke in people 49 and younger remained steady over the course of the study, with around 21 cases of ischemic stroke per 100,000 person-years at the start and end of the study. For intracerebral hemorrhage, the incidence rate in young people was around 2 cases per 100,000 person-years at the start and end of the study. The incidence rates of stroke declined in people 50 and older over the course of the study, with 372 cases of ischemic stroke per 100,000 person-years at the start of the study and 311 cases at the end. For intracerebral hemorrhage, there were 49 cases per 100,000 person-years at the start of the study and 38 cases at the end. However, stroke rates in people in their 50s were stable, with most of the decline in people age 70 and older.

"The improvements we found in survival rates are consistent with improvements in stroke care. We also examined stroke severity and found while mild strokes increased, the most severe cases declined. These changes could be related to improvements in stroke awareness in the general population as well as the care people receive for stroke, including in the ambulance and emergency department prior to hospitalization. Such care has led to faster and improved diagnostics, particularly regarding the mildest of cases."

Recent studies have shown that exercise improves skeletal muscle and cognitive function by stimulating the secretion of numerous molecules. In particular, previous studies have suggested that exercise-induced beta-hydroxybutyrate (BHB) release might improve skeletal muscle and cognitive function, but to date these studies have been limited to cell models and animal models. Therefore, we aimed to determine how an exercise-induced increase in BHB affects skeletal muscle and cognitive function at a cellular level, in an animal model, and in humans. The effects of BHB on skeletal muscle and cognitive function were determined by treating muscle and glial cell lines with BHB, and by measuring the skeletal muscle and serum BHB concentrations in aged mice after endurance or resistance exercise. In addition, serum BHB concentration was measured before and after high-speed band exercise in elderly people, and its relationships with muscle and cognitive function were analyzed.

We found that BHB increased cell viability and brain-derived neurotrophic factor expression level in glial cells, and endurance exercise, but not resistance exercise, increased the muscle BHB concentration in aged mice. Furthermore, the BHB concentration was positively related to skeletal muscle and cognitive function. Exercise did not increase the serum BHB concentration in the elderly people and BHB did not correlate with cognitive function, but after excluding the five people with the highest preexisting serum concentrations of BHB, the BHB concentrations of the remaining participants were increased by exercise, and the concentration showed a tendency toward a positive correlation with cognitive function. Thus, the BHB released by skeletal muscle following endurance exercise may improve muscle and cognitive function in animals and humans.

There is a heterogeneity in markers expressed by senescent cells depending on both cell type and an insult used to induce senescence. However, there are several common features typical for the most types of senescent cells. The essential characteristic of senescence for any kind of dividing cells is the irreversible proliferation loss. The irreversibility of the cell cycle arrest is controlled by the cyclin-dependent kinase (CDK) inhibitors p16 and p21 and is often regulated by the tumor suppressor protein p53.

The other important features of senescent cells are the activation of a persistent DNA damage response; cell hypertrophy, which often arises as a result of impaired ribosomal biogenesis and protein synthesis; disturbance of lysosomal degradation and dysfunction of the rest degradation systems; increased activity of the specific lysosomal enzyme senescence-associated-β-galactosidase; various mitochondrial alterations; acquisition of the senescence-associated secretory phenotype.

Targeted elimination of senescent cells - senolysis - is one of the core trends in the anti-aging therapy. Cardiac glycosides were recently proved to be broad-spectrum senolytics. Here we tested senolytic properties of cardiac glycosides towards human mesenchymal stem cells (hMSCs). Cardiac glycosides had no senolytic ability towards senescent hMSCs of various origins. Using biological and bioinformatic approaches we compared senescence development in 'cardiac glycosides-sensitive' A549 cells and '-insensitive' hMSCs. The absence of senolysis was found to be mediated by the effective potassium import and increased apoptosis-resistance in senescent hMSCs.

We revealed that apoptosis-resistance, previously recognized as a common characteristic of senescence, in fact, is not a general feature of senescent cells. Moreover, only apoptosis-prone senescent cells are sensitive to cardiac glycosides-induced senolysis. Thus, we can speculate that the effectiveness of senolysis might depend on whether senescent cells indeed become apoptosis-resistant compared to their proliferating counterparts.

Heart disease is the leading cause of death globally and prevention is a major public health priority. The beneficial impact of physical activity in stopping heart disease and sudden death on a population level is well documented. This study focused on the effect of an active versus sedentary lifestyle on the immediate course of a heart attack - an area with little information.

The researchers used data from 10 European observational cohorts including healthy participants with a baseline assessment of physical activity who had a heart attack during follow-up - a total of 28,140 individuals. Participants were categorised according to their weekly level of leisure-time physical activity as sedentary, low, moderate, or high. The association between activity level and the risk of death due to a heart attack (instantly and within 28 days) was analysed in each cohort separately and then the results were pooled.

A total of 4,976 (17.7%) participants died within 28 days of their heart attack - of these, 3,101 (62.3%) died instantly. Overall, a higher level of physical activity was associated with a lower risk of instant and 28-day fatal heart attack, seemingly in a dose-response-like manner. Patients who had engaged in moderate and high levels of leisure-time physical activity had a 33% and 45% lower risk of instant death compared to sedentary individuals. At 28 days these numbers were 36% and 28%, respectively. The relationship with low activity did not reach statistical significance.

Recent work on senescent cell dynamics with age used these dynamics to explain the distribution of death times in mice and humans. It was shown that senescent cells are produced and removed with a half-life of days in young mice, but their removal rate slows down in old mice to a half-life of weeks. These data, together with longitudinal measurement of senescent cells in mice, were used to develop a stochastic model for senescent-cell production and removal, called the saturated-removal (SR) model. The SR model shows that senescent cells slow their own removal rate, which leads to wide variations between individuals in the number of senescent cells at old ages. Assuming that death occurs when senescent cells exceed a threshold, it was shown that the SR model explains the distribution of times of death.

Since senescent cells are implicated in many age-related diseases, and since a threshold-crossing event of senescent cells in the SR model has an exponentially rising probability with age, we asked whether age-related diseases can be modeled as a threshold-crossing phenomenon in which senescent cells exceed a disease-specific threshold. To explain the drop in incidence at very old ages, we add to this model the epidemiological notion of heterogeneity, in which some people are more susceptible to the disease than others. We show that the SR model with differential susceptibility provides a model with 2 or 3 free parameters that can explain a wide range of age-related incidence curves. This includes the incidence of many types of cancer, major fibrotic diseases, and hundreds of other age-related disease states obtained from a large-scale medical record database.

This conceptual picture explains why different diseases have similar exponential rise in incidence and a drop at very old ages, based on a shared biological process, the accumulation of senescent cells. It also can be used to optimize the frequency of treatments that eliminate senescent cells, showing that even infrequent treatment starting at old age can reduce the incidence of a wide range of diseases.

Senescent cells, which show the permanent growth arrest in response to various forms of stress, accumulate in the body with the progression of age, and are associated with aging and age-associated diseases. Although the senescent cells are growth arrested, they still demonstrate high metabolic rate and altered gene expression, indicating that senescent cells are still active. We recently showed that the circadian clock properties, namely phase and period of the cells, are altered with the establishment of replicative senescence. However, whether cellular senescence triggers the alteration of circadian clock properties in the cells is still unknown.

In this study we show that the oxidative stress-induced premature senescence induces the alterations of the circadian clock, similar to the phenotypes of the replicative senescent cells. We found that the oxidative stress-induced premature senescent cells display the prolonged period and delayed phases. In addition, the magnitude of these changes intensified over time, indicating that cellular senescence changes the circadian clock properties. Our current results corroborate with our previous findings and further confirm that cellular senescence induces altered circadian clock properties, irrespective of the replicative senescence or the stress-induced premature senescence.