Fight Aging! Newsletter, September 6th 2021

Aging is characterized by an accumulation of chronic diseases and conditions, including poor oral health, which can influence quality of life and health. Oral health problems, including tooth loss, periodontal disease, and dry mouth, accumulate throughout adult life and worsen with increasing age3. Poor dental health is associated with high levels of inflammation, poor diet quality, and conditions such as disability, diabetes, and increased risk of cardiovascular disease (CVD) and pneumonia.

Furthermore, studies have suggested that poor oral health is associated with higher risk of mortality, including major causes of death such as CVD and respiratory diseases or infections. Tooth loss and periodontal disease have been reported to be associated with increased risks of all-cause, CVD, and respiratory mortality in community-dwelling middle-aged and older people. Furthermore, poor self-rated oral health was found to be associated with increased risk of all-cause mortality in a population of middle-aged and older adults.

We used cohort data from the British Regional Health Study (BRHS) (N = 2147, 71-92 years), and the US Health, Aging, and Body Composition (HABC) Study (N = 3075, 71-80 years). Follow-up was 9 years (BRHS) and 15 years (HABC Study). Oral health comprised tooth loss, periodontal disease, dry mouth, and self-rated oral health. Cox regression was performed for all-cause mortality, competing risks for CVD mortality, and accelerated failure time models for respiratory mortality.

In the BRHS, tooth loss was associated with all-cause mortality (hazard ratio = 1.59). In the HABC Study, tooth loss, dry mouth, and having ≥ 3 oral problems were associated with all-cause mortality; periodontal disease was associated with increased CVD mortality (subdistribution hazard ratio = 1.49); tooth loss, and accumulation of oral problems were associated with high respiratory mortality (time ratio = 0.73). Findings suggest that poor oral health is associated with mortality.

Mitochondria produce the energy needed to drive nearly all processes in living cells. Cardiac muscle cells contain more mitochondria than any other cells, because the heart needs large amounts of energy to constantly pump blood throughout the body. Stable mitochondrial dynamics maintain a healthy balance between the constant division (fission) and merging (fusion) of mitochondria and help ensure the quality of these specialized structures known as the "powerhouse" of the cell.

Reperfusion, a common treatment following acute heart attack, restores blood flow (and thus oxygen) to a region of the heart damaged by a blood clot blocking the coronary artery. Paradoxically, in some patients this necessary revascularization procedure triggers further injury to heart muscle tissue surrounding the initial heart attack site. No effective therapies currently exist to prevent reperfusion injury.

To help analyze the response of cardiac mitochondria to ischemia-reperfusion stress, researchers deleted SIRT1 or SIRT3 in cardiac muscle cells of mouse hearts, and examined the mitochondrial response to ischemic stress by restricted blood flow. The researchers found that the mitochondria in mouse hearts lacking cardiomyocyte SIRT3 were more vulnerable to reperfusion stress than the mouse hearts with SIRT3 intact. The cardiac mitochondrial dynamics (including shape, size, and structure of mitochondria) in these knockout mice physiologically resembled that of aged wildtype (normal) mice retaining cardiac SIRT3.

Furthermore, the young mice with SIRT1 or SIRT3 removed had measurably weaker cardiomyocyte contractions and exhibited aging-like heart dysfunction when ischemia-reperfusion stress was introduced. In essence, without SIRT1/SIRT3 the hearts of these otherwise healthy young mice looked and behaved like old hearts.

Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) protects cardiac function against ischemia/reperfusion (I/R) injury. Mitochondria are critical in response to myocardial I/R injury as disturbance of mitochondrial dynamics contributes to cardiac dysfunction. It is hypothesized that SIRT1 and SIRT3 are critical components to maintaining mitochondria homeostasis, especially mitochondrial dynamics, to exert cardioprotective actions under I/R stress. The results demonstrated that deficiency of SIRT1 and SIRT3 in aged (24-26 months) mice hearts led to the exacerbated cardiac dysfunction in terms of cardiac systolic dysfunction, cardiomyocytes contractile defection, and abnormal cardiomyocyte calcium flux during I/R stress. Moreover, the deletion of SIRT1 or SIRT3 in young (4-6 months) mice hearts impair cardiomyocyte contractility and shows aging-like cardiac dysfunction upon I/R stress, indicating the crucial role of SIRT1 and SIRT3 in protecting myocardial contractility from I/R injury.

The lack of physical exercise (PE) is a common phenomenon in modern society and has become a risk factor for many diseases, including cardiovascular diseases, metabolic dysfunctions, cancers, and neurodegenerative diseases. Appropriate exercise shapes the athletic figure and improves the body's basal metabolic rate. PE also plays a vital role in brain health, especially in preventing and alleviating the decline of cognitive function as well as the occurrence of some neurodegenerative diseases. The positive effects of regular, long-term physical activities and exercise interventions on cognition have been reported in the literature. Since only limited therapies are available for cognitive impairment, exercise may serve as a promising non-pharmaceutical treatment.

The process of brain aging, which is one of the risk factors for neurodegeneration, has been found to involve epigenetic mechanisms. Epigenetics, by definition, refers to a set of heritable mechanisms and phenomena that determine cell phenotypes without changing the genome. Epigenetic modifications such as abnormal DNA methylation (DNAm), microRNAs, and histone modifications are closely associated with damage to brain health and neurodegenerative diseases. As individuals age, the age-related changes are often linked to the fluctuating methylation levels of specific genes.

The DNAm has been proposed as a potential multi-tissue estimator of biological age and the concept of epigenetic clock (i.e., DNAm clock) has been developed with a suitable regression model to systemically measure the biological age. This tool has been extensively applied to distinguish between chronological age and biological age, as well as to estimate the corresponding health/disease status. While healthy individuals have almost identical chronological age and biological age (normal aging), patients with cancer and neurodegenerative diseases are biologically older (pathologic aging) and the offspring of centenarians are biologically younger (delayed aging). Therefore, the epigenetic clock is capable of assessing the state of aging among populations. Moreover, DNAm is associated with environmental and lifestyle factors, which have the capacity for regulating epigenetic variability in the brain. Given the effects of such factors as PE in slowing down the epigenetic age acceleration or even resetting the aging clock, the epigenetic clock has progressively become an exciting area of research.

In this review, we summarize brain-specific, disease-related mechanisms involving DNAm, through which PE reverses epigenetic changes to ameliorate neurodegeneration in aging, AD, and PD. We also integrate data from muscular-related molecule cascades in the periphery, which are directly induced by PE to affect the central nervous system (CNS). Furthermore, as a potential mediator of motor skills, DNAm can be modulated to improve the pathological symptoms of dyskinesia-related neurodegenerative diseases. The role of PE in neurodegeneration is further explored from the perspective of epigenetic-related mechanisms, and PE can be viewed as a potential rejuvenation therapy.

The numerous beneficial health outcomes associated with the use of metformin to treat patients with type 2 diabetes (T2DM), together with data from pre-clinical studies in animals including the nematode, C. elegans, and mice have prompted investigations into whether metformin has therapeutic utility as an anti-aging drug that may also extend lifespan. Indeed, clinical trials, including the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), have been designed to assess the potential benefits of metformin as an anti-aging drug.

Preliminary analysis of results from MILES indicate that metformin may induce anti-aging transcriptional changes; however it remains controversial as to whether metformin is protective in those subjects free of disease. Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts its actions remain unclear. In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan, and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin.

We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline, and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.

The gut microbiota plays a key role in modulating the gut-brain axis, which is a bidirectional communication network that involves the central nervous system, the autonomic nervous system (sympathetic and parasympathetic branches), the enteric nervous system, and the hypothalamic-pituitary-adrenal axis. Recent advances have revealed that the microbiota of the human gut has numerous beneficial functions, such as immune system development, resistance to pathogens, vitamin synthesis, production of metabolites such as short-chain fatty acids (SCFAs), nutrient and drug metabolism, and maintenance of the structural integrity of the intestinal mucosal barrier.

In humans, dysbiosis and changes in gut microbiome composition have been found to contribute to inflammatory bowel disease, type 2 diabetes, metabolic syndrome, obesity, colorectal cancer, Alzheimer's disease (AD), and numerous other diseases. AD is a disastrous neurological disorder affecting 5.8 million Americans (aged 65 years or older) in 2020. AD was the sixth most common cause of death in 2017, accounting for 121,404 deaths in the United States, and the fifth most common cause of death among elderly Americans (65+ years). The sizeable economic burden of AD, as well as its growing prevalence, are leading researchers to look for preventive or disease-modifying treatments.

There are various gut microbiota modulation interventions such as diet modification, prebiotics, probiotics, synbiotics, or fecal microbiota transplantation (FMT). FMT includes the transplantation of the gut microbiota from a donor to a recipient to refurbish the intestinal microflora of the recipient. It has been proven to be a successful treatment for recurrent Clostridium difficile infections. In this review, we summarize the procedure of FMT and its application in the treatment of various neurological disorders with a special emphasis on AD.

The goal of this study was to investigate whether various aspects of bone health among the very elderly could provide insight into the aging process in this unique population. Our study investigated the prominence of fractures, osteopenia, and osteoporosis among our study population and made comparative analyses specifically looking at metabolic values and blood indices characteristic of bone health as well as the impact of prescribed medication therapies.

Overall, we found a low rate of fractures in our group of patients over 90 years of age. The distribution of fractures found in our study correlates with the expected distribution of fractures for an elderly cohort, with the most common occurring at the spine and hip. Additionally, there was a trend toward lower incidence of fracture among the oldest individuals, as compared to the general very old population in the United States. The incidence for hip fractures in the ≥100-year-old population has been estimated to be 23.1 per 1000 individuals per year (2.3% per year), whereas our study found a fracture incidence of 1.9% per year among our population of very elderly individuals. This indicates that our population of nonagenarians may have characteristics that contributed to the preservation of bone health even into extreme old age.

In conclusion, patients over 90 years of age had an overall low prevalence of fractures and relative preservation of bone health, suggesting a preserved bone molecular profile in these individuals. Epigenetic factors and activity levels might also have favorably affected bone health. The low percentage of osteoporosis and fractures likely reduced the morbidity and mortality in this population, potentially contributing to their overall longevity.

Key to Genflow's approach is a collaboration with Vera Gorbunova - a member of the company's scientific advisory board, and well known for her research into SIRT6. "In 2019, Vera published a paper that showed, in rodents, you could have a very good correlation between lifespan and the quality of SIRT6. She found she could increase or decrease the lifespan of rodents based on the variant of SIRT6 that she was providing." This led researchers wonder whether it was possible to find a "better" SIRT6 than the one that already exists in humans. "We discovered that it was possible, thanks to the discovery of a variant of SIRT6 only found in centenarians. So we decided to create a company that will deliver this SIRT6 variant in order to prevent the accelerated aging process."

"Ten years ago, gene therapy was a bad word associated with high cost and high toxicity - a dangerous last resort therapy. Now you see progress in AAVs every week. Today we have AAVs that are almost invisible to the immune system, they are non-integrating, their cost has decreased substantially, and there are now more than 40 companies developing clinical trials with AAVs. So, it's now possible to have an ethical, patient friendly and cost-effective intervention at the genetic level."

While progeria, Werner's syndrome, and other indications are in the company's pipeline for eventual human trials, Genflow is really only thinking about targeting aging. "One of the differences between us and other longevity companies is that we are fully dedicating to longevity. Yes, we will have a trial in Werner's syndrome, but we consider that a door opener to having a true aging indication. At one point, we know that the regulatory agencies will change their mindset on this - we see an evolution - and we want to be positioned to be to take advantage of that."

A few geroprotective drugs exist that postpone age-related diseases. For instance, the anti-diabetes drug metformin reduces age-related chronic diseases and mortality from all causes. Ongoing clinical trials on geroprotective drugs or compounds include the anti-diabetic drugs metformin and acarbose; mTOR-inhibiting and immunosuppressant drug rapamycin; natural compounds resveratrol and urolithin A; and nicotinamide adenine dinucleotide precursors NR and NMN. One primary outcome measure used in the aforementioned clinical trials for metformin and acarbose is the restoration from an "old" to a "youthful" gene expression signature. Therefore, we reasoned that cross-comparing youthful expression signatures against expression profiles elicited by small molecules could identify geroprotective compounds.

A key signature of aging is the continuous decline of collagen and cell adhesion gene expression accompanied with an increase in matrix metalloproteinase expression. Gene expression ontologies of extracellular matrix (ECM) genes have been associated with healthy aging in humans. The ECM not only embeds cells and tissues but also provides instructive cues that change cellular function and identity. For instance, placing old cells into a "young" ECM rejuvenates senescent cells or stem cells and even reprograms tumor cells. Moreover, collagen homeostasis is required and sufficient for longevity in Caenorhabditis elegans. Chondroitin biosynthesis and TGFβ pathway are frequently enriched in C. elegans longevity drug screens. Collectively, these functionally implicated genes are all members of the matrisome.

To harness this observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a "youthful" matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for Caenorhabditis elegans longevity. With this reporter, we were able to eliminate false-positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach - employing extracellular matrix homeostasis - facilitates the discovery of pharmacological interventions promoting healthy aging.

New work addresses a longstanding problem in the field of cancer immunotherapy: how to make chimeric antigen receptor (CAR) T-cell therapy safe and effective at treating solid tumors. CAR T-cell therapy is a promising new approach to treat cancer. It involves collecting a patient's T cells and genetically engineering them to express special receptors, called CAR, on their surface that recognize specific antigens on cancer cells. The resulting CAR T cells are then infused back into the patient to find and attack cells that have the cancer antigens on their surface.

This therapy has worked well for the treatment of some blood cancers and lymphoma, but not against solid tumors. That's because many of the target antigens on these tumors are also expressed on normal tissues and organs. This can cause toxic side effects that can kills cells - these effects are known as on-target, off-tumor toxicity. To combat this issue, the team took standard CAR T cells and re-engineered them so that they only express the CAR protein when ultrasound energy is applied. This allowed the researchers to choose where and when the genes of CAR T cells get switched on. Ultrasound can penetrate tens of centimeters beneath the skin, so this type of therapy has the potential to non-invasively treat tumors that are buried deep inside the body.

The team's approach involves injecting the re-engineered CAR T cells into tumors in mice and then placing a small ultrasound transducer on an area of the skin that's on top of the tumor to activate the CAR T cells. The transducer uses focused ultrasound beams to focus or concentrate short pulses of ultrasound energy at the tumor. This causes the tumor to heat up moderately - in this case, to a temperature of 43 degrees Celsius (109 degrees Fahrenheit) - without affecting the surrounding tissue. The CAR T cells in this study are equipped with a gene that produces the CAR protein only when exposed to heat. As a result, the CAR T cells only switch on where ultrasound is applied.

Osteoarthritis (OA), the most common aging-related joint disease, is caused by an imbalance between extracellular matrix synthesis and degradation. Here, we discover that both strands of microRNA-455 (miR-455), -5p and -3p, are up-regulated by Sox9, an essential transcription factor for cartilage differentiation and function. Both miR-455-5p and -3p are highly expressed in human chondrocytes from normal articular cartilage and in mouse primary chondrocytes.

We generate miR-455 knockout mice, and find that cartilage degeneration mimicking OA and elevated expression of cartilage degeneration-related genes are observed at 6-months-old. Using a cell-based miRNA target screening system, we identify hypoxia-inducible factor-2α (HIF-2α), a catabolic factor for cartilage homeostasis, as a direct target of both miR-455-5p and -3p. In addition, overexpression of both miR-455-5p and -3p protect cartilage degeneration in a mouse OA model, demonstrating their potential therapeutic value. Furthermore, knockdown of HIF-2α in 6-month-old miR-455 knockout cartilage rescues the elevated expression of cartilage degeneration-related genes.

This data strongly implicates miR-455-5p and -3p in supporting articular cartilage homeostasis by targeting Hif-2α.

Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by a selective type of macroautophagy, named mitophagy. One of the main factors contributing to aging is oxidative stress, and one of the early responses to excessive reactive oxygen species (ROS) production is the induction of mitophagy to remove damaged mitochondria. However, mitochondrial damage caused at least in part by chronic oxidative stress can accumulate, and autophagic and mitophagic pathways can become overwhelmed. The imbalance of the delicate equilibrium among mitophagy, ROS production, and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological aging, or in pathological age-related conditions, such as Alzheimer's and Parkinson's diseases.

The interplay between mitophagy, ROS production, and aging is complex and far from being completely elucidated. The central role of ROS production and consequent damage to mitochondria in the aging process has been clearly established in the last 50 years, despite some objections to this theory over the past 15 years, and mitophagy is a key mechanism for mitochondrial quality and quantity control, as it limits the production of ROS, the damage to mitochondrial DNA of transmembrane potential loss, and the decrease in ATP production.

Evidence indicates that the imbalance of the delicate equilibrium among mitophagy, ROS production, and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological or pathological conditions. It remains to be determined which is the prime mover of this imbalance, i.e., whether it is the mitochondrial damage caused by ROS that initiates the dysregulation of mitophagy, thus activating a vicious circle that leads to the reduced ability to remove damaged mitochondria, and further damage from ROS, or if, on the other hand, an alteration in the regulation of mitophagy constitutes one of the initial events leading to the main of the excessive production of ROS.

A number of features of senescence have been characterized, which could be used as proper biomarkers or potential therapeutic targets. Senescent cells generally display dramatically morphological changes, increased β-galactosidase activity, stable cell cycle arrest, persistent DNA damage response, metabolic reprogramming, and significant chromatin remodeling. The secretion of senescence-associated secretory phenotype (SASP) factors change the tissue microenvironment and affect even remote tissue via paracrine mechanisms, which is believed to contribute to organ degeneration with aging.

The phenotypic manifestations of SASP are heterogeneous and induced by different internal and external stimulus including telomere attrition, DNA damage, oncogenic activation, mitochondrial dysfunction, or epigenetic alterations. The SASP factors are mainly made of different types of soluble components including pro-inflammatory cytokines, growth factors, chemokines, and extracellular matrix-degrading proteins. This particular combination of signaling factors and the proteases that degrade extracellular matrix (ECM) to facilitate signal transduction has made SASP a powerful mechanism to modulate intercellular communication. The secretion of SASP factors is considered as a major detrimental aspect of senescence because it promotes chronic inflammation, induces fibrosis, and causes stem cell exhaustion.

However, it has also been shown to favor embryonic development or wound healing, suggesting whether beneficial or detrimental effects the SASP exerts depends on the physiological and pathological context. For example, a recent study has shown that transiently exposing the primary mouse keratinocytes to SASP factors increased cell stemness and regenerative capacity in vivo, while prolonged exposure caused secondary senescence and hindered regeneration. This suggests senescence has more complicated physiological roles than currently understood.

Senescence and its secretion phenotype SASP are the most fundamental player that could systematically change physiological functions at the intercellular level and reshape the tissue microenvironment toward aging. They directly change compositions of cell population by arresting the proliferation of progenitor cells or release pro-inflammatory factors to chronically elevate basal inflammation level causing systematic inflammaging. The effects of senescence and SASP are "erosive." Once it starts, it has the potential to spread via the flowing cytokines to induce remote secondary senescence.

Elimination of senescent cells by senolytic drugs has been proven to be effective to counteract senescence in natural aging or age-related disease model. Recently, the first clinical trial of senolytic drug was conducted in human with idiopathic pulmonary fibrosis (IPF). Surprisingly, instead of rescuing lung functions, there was significant improvement in locomotor function such as walking distance or gait speed. Although it is a mystery why the drug failed to take effect in lungs where the most of senescent cells exist in IPF patients, it is still exciting to see the improvement in motor functions which proved senescence communicates at inter-tissue levels. In the future, increasing the specificities of senolytic drugs might help to better cure aging-related diseases.

Aging causes loss of skeletal muscle mass and function, which is called sarcopenia. While sarcopenia impairs the quality of life of older adults and is a major factor in long-term hospitalization, its detailed pathogenic mechanism and preventive measures remain to be identified. Caloric restriction (CR) suppresses age-related physiological and pathological changes in many species and prolongs the average and healthy life expectancy. It has recently been reported that CR suppresses the onset of sarcopenia; however, few studies have analyzed the effects of long-term CR on age-related skeletal muscle atrophy. Thus, we investigated the aging and CR effects on soleus (SOL) muscles of 9-, 24-, and 29-month-old ad libitum-fed rats (9AL, 24AL, and 29AL, respectively) and of 29-month-old CR (29CR) rats.

The total muscle cross sectional area (mCSA) of the entire SOL muscle significantly decreased in the 29AL rats, but not in the 24AL rats, compared with the 9AL rats. SOL muscle of the 29AL rats exhibited marked muscle fiber atrophy and increases in the number of muscle fibers with a central nucleus, in fibrosis, and in adipocyte infiltration. Additionally, although the decrease in the single muscle fiber cross-sectional area (fCSA) and the muscle fibers' number occurred in both slow-type and fast-type muscle fibers, the degree of atrophy was more remarkable in the fast-type fibers.

However, CR suppressed the muscle fiber atrophy observed in the 29AL rats' SOL muscle by preserving the mCSA and the number of muscle fibers that declined with aging, and by decreasing the number of muscle fibers with a central nucleus, fibrosis, and denervated muscle fibers. Overall, these results revealed that advanced aging separately reduces the number and fCSA of each muscle fiber type, but long-term CR can ameliorate this age-related sarcopenic muscle atrophy.

The muscle cells in healthy blood vessels are elastic and can stretch like rubber bands, allowing high volumes of blood to pump through. When the blood vessel tissues lose their elasticity, the vessels stiffen, forcing the heart to work harder to pump blood throughout the body. While diet, exercise and medication can improve overall heart health, there are no drugs on the market to treat underlying stiffening in blood vessels.

Most research into blood vessel stiffening has focused on the material surrounding the living cells - called the extracellular matrix - as the most important contributor to this condition. However, researchers now lay out evidence that smooth muscle cells independently contribute to vascular stiffening. To study this connection, the researchers first had to cut the line of communication between cells and the surrounding matrix. They used a gene editing tool called CRISPR to breed mice lacking the gene that produces transglutaminase (TG2), an enzyme enabling this crosstalk to take place.

Compared with mice that had normal TG2 production, the researchers found that in mice with no TG2 - where the crosstalk between the matrix and vascular smooth muscle cells was uncoupled - the development of vascular stiffening was reduced by nearly 70% at age 15 months. This is old age for a mouse and, generally, the time when blood vessels stiffen. The researchers say this indicates smooth muscle cells independently contribute to vascular stiffening, and that crosstalk influences vascular aging. Researchers suspect that severe vascular stiffening, like that seen in humans of old age, could be caused by out-of-control feedback between smooth muscle cells and their surrounding matrix.

Osteoporosis or porous bone disorder is the result of an imbalance in an otherwise highly balanced physiological process known as 'bone remodeling'. The immune system is intricately involved in bone physiology as well as pathologies. Inflammatory diseases are often correlated with osteoporosis. Inflammatory mediators such as reactive oxygen species (ROS), and pro-inflammatory cytokines and chemokines directly or indirectly act on the bone cells and play a role in the pathogenesis of osteoporosis.

Recently, researchers have coined the term "immunoporosis" to emphasize the role of immune cells in the pathology of osteoporosis. Accumulated evidence suggests both innate and adaptive immune cells contribute to osteoporosis. However, innate cells are the major effectors of inflammation. They sense various triggers to inflammation such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), cellular stress, etc., thus producing pro-inflammatory mediators that play a critical role in the pathogenesis of osteoporosis.

Cells of the myeloid lineage, including macrophages, monocytes, and dendritic cells, explicitly influences the skeletal system by the action of production of pro-inflammatory cytokines and can transdifferentiate into osteoclasts. Other cells of the myeloid lineage, such as neutrophils, eosinophils, and mast cells, largely impact osteoporosis via the production of pro-inflammatory cytokines. Further, cells of the lymphoid lineage, including natural killer cells and innate lymphoid cells, share innate-like properties and play a role in osteoporosis.