Pathological Aging Research Articles

Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies.

TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterize TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use data-driven disease progression modelling to derive a fine-grained empirical staging system for the classification and differentiation of frontotemporal lobar degeneration due to TDP-43 (FTLD-TDP, n = 126), amyotrophic lateral sclerosis (ALS, n = 141) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) with and without Alzheimer's disease (n = 304). The data-driven staging of ALS and FTLD-TDP complement and extend previously described human-defined staging schema for ALS and behavioural variant frontotemporal dementia. In LATE-NC individuals, progression along data-driven stages was positively associated with age, but negatively associated with age in individuals with FTLD-TDP. Using only regional TDP-43 severity, our data driven model distinguished individuals diagnosed with ALS, FTLD-TDP or LATE-NC with a cross-validated accuracy of 85.9%, with misclassifications associated with mixed pathological diagnosis, age and genetic mutations. Adding age and SuStaIn stage to this model increased accuracy to 92.3%. Our model differentiates LATE-NC from FTLD-TDP, though some overlap was observed between late-stage LATE-NC and early-stage FTLD-TDP. We further tested for the presence of subtypes with distinct regional TDP-43 progression patterns within each diagnostic group, identifying two distinct cortical-predominant and brainstem-predominant subtypes within FTLD-TDP and a further two subcortical-predominant and corticolimbic-predominant subtypes within ALS. The FTLD-TDP subtypes exhibited differing proportions of TDP-43 type, while there was a trend for age differing between ALS subtypes. Interestingly, a negative relationship between age and SuStaIn stage was seen in the brainstem/subcortical-predominant subtype of each proteinopathy. No subtypes were observed for the LATE-NC group, despite aggregating individuals with and without Alzheimer's disease and a larger sample size for this group. Overall, we provide an empirical pathological TDP-43 staging system for ALS, FTLD-TDP and LATE-NC, which yielded accurate classification. We further demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns that warrants further investigation in larger cross-cohort studies.

LncRNA TRHDE-AS1 Correlated with Genomic Landscape and Clinical Outcome in Glioma.

The role of lncRNA in cancer development has received more and more attention in research. A variety of lncRNAs are associated with the occurrence and development of glioma. However, the role of TRHDE-AS1 in glioma is still unknown. In this study, we explored the role of TRHDE-AS1 in glioma through bioinformatic methods. We first identified an association between TRHDE-AS1 and tumor prognosis in pan-cancer analysis. Subsequently, the expression levels of TRHDE-AS1 in various clinical types of glioma were compared, and significant differences were found in pathological classification, WHO classification, molecular classification, IDH mutation, and age stratification. We analyzed the genes co-expressed with TRHDE-AS1 in glioma. In the functional analysis of TRHDE-AS1, we found that TRHDE-AS1 may be involved in the regulation of synapse-related functions. In glioma cancer driver gene correlation analysis, it was also found that TRHDE-AS1 was significantly correlated with the expression levels of multiple driver genes such as TP53, BRAF, and IDH1. By comparing the mutant profiles of the high and low TRHDE-AS1 groups, we also found that there may be differences in TP53 and CIC gene mutations in low-grade gliomas. Subsequent correlation analysis between TRHDE-AS1 and glioma immune microenvironment showed that the expression level of TRHDE-AS1 was correlated with a variety of immune cells. Therefore, we believe that TRHDE-AS1 is involved in the occurrence and development of glioma and has the ability to predict the prognosis of glioma as a biomarker of glioma.

Association between Age Gain, Parkinsonism and Pesticides: A Public Health Problem?

As life expectancy increases worldwide, so does the time available for prolonged exposure to toxic materials in the environment that have the potential to exert gradual pressure, facilitating the onset of aging in the body.
 Neural/behavioral alterations are linked to age gain, making the understanding of the aging process more complex considering the high complexity of the neural system and, although neuropsychological, pathological and neuroimaging criteria have been established to differentiate between normal and pathological aging, diagnosing the mild cognitive problems of each elderly individual remains a challenge.
 Parkinson's disease is recognized as one of the most common neurological disorders in the elderly, whose intrinsic cause is still unknown, but its main molecular basis is the decrease in dopamine produced in the substantia nigra. Studies have suggested that exposure to organophosphate, the glyphosate class, in different organisms, are capable of promoting bodily malformations, neurotoxicity, hepatotoxicity, genotoxicity, metabolic disorders, among others. The effects of pesticides on the environment, associated with their exacerbated permanence in the environment, indicate that more and more people may suffer their deleterious action, which may be the cause of some neurodegenerative disorders. The main objective of this study was to use specific data from the literature on Parkinsonism, correlating it with aging and contamination by pesticides.
 In fact, the health risks inherent in the use of pesticides are greater the greater the intensity of exposure to them and, considering the widespread use of pesticides today, the number of poisoning of the human population and animals will increase. Therefore, in terms of literary data, contamination with pesticides may be associated with a public health problem and, therefore, a possible increase in dementia processes, thus Parkinsonism.

Slope of the power spectral density flattens at low frequencies (200Hz) in human electroencephalogram.

The power spectral density (PSD) of the brain signals is characterized by two distinct features: oscillations, which are represented as distinct "bumps," and broadband aperiodic activity, that reduces in power with increasing frequency and is characterized by the slope of the power falloff. Recent studies have shown a change in the slope of the aperiodic activity with healthy aging and mental disorders. However, these studies analyzed slopes over a limited frequency range (<100Hz). To test whether the PSD slope is affected over a wider frequency range with aging and mental disorder, we analyzed the slope till 800Hz in electroencephalogram data recorded from elderly subjects (>49years) who were healthy (n = 217) or had mild cognitive impairment (MCI; n = 11) or Alzheimer's Disease (AD; n = 5). Although the slope reduced up to ~ 150Hz with healthy aging (as shown previously), surprisingly, at higher frequencies (>200Hz), it increased with age. These results were observed in all electrodes, for both eyes open and eyes closed conditions, and for different reference schemes. However, slopes were not significantly different in MCI/AD subjects compared with healthy controls. Overall, our results constrain the biophysical mechanisms that are reflected in the PSD slopes in healthy and pathological aging.

Natural and Pathological Aging Distinctively Impacts the Pheromone Detection System and Social Behavior

Normal aging and many age-related disorders such as Alzheimer’s disease cause deficits in olfaction; however, it is currently unknown how natural and pathological aging impacts the detection of social odors which might contribute to the impoverishment of social behavior at old age further worsening overall health. Analysis of the vomeronasal organ, the main gateway to pheromone-encoded information, indicated that natural and pathological aging distinctively affects the neurogenic ability of the vomeronasal sensory epithelium. Whereas cell proliferation remained majorly preserved in 1-year-old APP/PS1 mice, naturally aged animals exhibited significant deficiencies in the number of mature, proliferative, and progenitor cells. These alterations may support age-related deficits in the recognition of social cues and the display of social behavior. Our findings indicate that aging disrupts the processing of social olfactory cues decreasing social odor exploration, discrimination, and habituation in both wild-type senescent (2-year-old) mice and in 1-year-old double mutant model of Alzheimer’s disease (APP/PS1). Furthermore, social novelty was diminished in 1-year-old APP/PS1 mice, indicating that alterations in the processing of social cues are accelerated during pathological aging. This study reveals fundamental differences in the cellular processes by which natural and pathological aging disrupts the exploration of social information and social behavior.

The Future of Cognitive Screening in Neurodegenerative Diseases.

Cognitive screening instruments (CSI) have variable sensitivity and specificity to the cognitive changes associated with dementia syndromes, and the most recent systematic review found insufficient evidence to support the benefit of cognitive screening tools in older adults residing within the community. Consequently, there is a critical need to improve CSI methods, which have not yet incorporated advances in psychometrics, neuroscience, and technology. The primary goal of this article is to provide a framework for transitioning from legacy CSIs to advanced dementia screening measurement. In line with ongoing efforts in neuropsychology and the call for next-generation digital assessment for early detection of AD, we propose a psychometrically advanced (including application of item response theory methods), automated selective assessment model that provides a framework to help propel an assessment revolution. Further, we present a three-phase model for modernizing CSIs and discuss critical diversity and inclusion issues, current challenges in differentiating normal from pathological aging, and ethical considerations.

Spatial orientation, postural control and the vestibular system in healthy elderly and Alzheimer's dementia.

While extensive research has been advancing our understanding of the spatial and postural decline in healthy elderly (HE) and Alzheimer's disease (AD), much less is known about how the vestibular system contributes to the spatial and postural processing in these two populations. This is especially relevant during turning movements in the dark, such as while walking in our garden or at home at night, where the vestibular signal becomes central. As the prevention of falls and disorientation are of serious concern for the medical service, more vestibular-driven knowledge is necessary to decrease the burden for HE and AD patients with vestibular disabilities. The review briefly presents the current "non-vestibular based" knowledge (i.e. knowledge based on research that does not mention the "vestibular system" as a contributor or does not investigate its effects) about spatial navigation and postural control during normal healthy ageing and AD pathology. Then, it concentrates on the critical sense of the vestibular system and explores the current expertise about the aspects of spatial orientation and postural control from a vestibular system point of view. The norm is set by first looking at how healthy elderly change with age with respect to their vestibular-guided navigation and balance, followed by the AD patients and the difficulties they experience in maintaining their balance or during navigation. Vestibular spatial and vestibular postural deficits present a considerable disadvantage and are felt not only on a physical but also on a psychological level by all those affected. Still, there is a clear need for more (central) vestibular-driven spatial and postural knowledge in healthy and pathological ageing, which can better facilitate our understanding of the aetiology of these dysfunctions. A possible change can start with the more frequent implementation of the "vestibular system examination/rehabilitation/therapy" in the clinic, which can then lead to an improvement of future prognostication and disease outcome for the patients.

(Zu-)Hören mit alterndem Gehirn – eine kognitive Herausforderung

Hearing impairment has been recently identified as a major modifiable risk factor for cognitive decline in later life and has been becoming of increasing scientific interest. Sensory and cognitive decline are connected by complex bottom-up and top-down processes, a sharp distinction between sensation, perception, and cognition is impossible. This review provides a comprehensive overview on the effects of healthy and pathological aging on auditory as well as cognitive functioning on speech perception and comprehension, as well as specific auditory deficits in the 2 most common neurodegenerative diseases in old age: Alzheimer disease and Parkinson syndrome. Hypotheses linking hearing loss to cognitive decline are discussed, and current knowledge on the effect of hearing rehabilitation on cognitive functioning is presented. This article provides an overview of the complex relationship between hearing and cognition in old age.

Behavioral and Transcriptome Profiling of Heterozygous Rab10 Knock-Out Mice.

A central question in the field of aging research is to identify the cellular and molecular basis of neuroresilience. One potential candidate is the small GTPase, Rab10. Here, we used Rab10+/- mice to investigate the molecular mechanisms underlying Rab10-mediated neuroresilience. Brain expression analysis of 880 genes involved in neurodegeneration showed that Rab10+/- mice have increased activation of pathways associated with neuronal metabolism, structural integrity, neurotransmission, and neuroplasticity compared with their Rab10+/+ littermates. Lower activation was observed for pathways involved in neuroinflammation and aging. We identified and validated several differentially expressed genes (DEGs), including Stx2, Stx1b, Vegfa, and Lrrc25 (downregulated) and Prkaa2, Syt4, and Grin2d (upregulated). Behavioral testing showed that Rab10+/- mice perform better in a hippocampal-dependent spatial task (object in place test), while their performance in a classical conditioning task (trace eyeblink classical conditioning, TECC) was significantly impaired. Therefore, our findings indicate that Rab10 differentially controls the brain circuitry of hippocampal-dependent spatial memory and higher-order behavior that requires intact cortex-hippocampal circuitry. Transcriptome and biochemical characterization of these mice suggest that glutamate ionotropic receptor NMDA type subunit 2D (GRIN2D or GluN2D) is affected by Rab10 signaling. Further work is needed to evaluate whether GRIN2D mediates the behavioral phenotypes of the Rab10+/- mice. We conclude that Rab10+/- mice described here can be a valuable tool to study the mechanisms of resilience in Alzheimer's disease (AD) model mice and to identify novel therapeutical targets to prevent cognitive decline associated with normal and pathologic aging.

Adaptive Functioning Among Older Adults: The Essence of Information Processing Speed in Executive Functioning.

The current study investigated the degree to which information processing speed mediates the association between executive functioning and adaptive functioning among older adults. Cases (N = 239) were selected from a clinical database of neuropsychological evaluations. Inclusion criteria were age 60+ (M = 74.0, standard deviation = 6.9) and completion of relevant study measures. Participants were majority White (93%) women (53.1%). The Texas Functional Living Scale was used as a performance-based measure of adaptive functioning. Information processing speed was measured using the Coding subtest from the Repeatable Battery for the Assessment of Neuropsychological Status. Executive functioning performance was quantified using part B of the Trail Making Test, Controlled Oral Word Association Test, and Similarities and Matrix Reasoning subtests from the Wechsler Abbreviated Scale of Intelligence, second edition. Mediation models were assessed with bootstrapped confidence intervals. Information processing speed mediated all measures of executive functioning. Direct effects were significant for all models (ps < 0.03), suggesting that executive functioning maintained unique associations with adaptive functioning. Follow-up analyses indicated no evidence for moderation of the mediation models based on diagnostic group. Additional models with executive functioning mediating information processing speed and adaptive functioning revealed inconsistent mediation, with smaller effects. Results highlight the importance of information processing speed in understanding real-world implications of pathological and non-pathological cognitive aging. Information processing speed mediated all relationships between executive functioning and adaptive functioning. Further investigation is warranted into the importance of processing speed in explaining associations of other cognitive domains with adaptive functioning.

What’s changing from normal aging to pathological aging during semantic memory retrieval: insights from EEG oscillations (S8.006)

<h3>Objective:</h3> To examine differences in EEG oscillations between normal cognitive aging versus pathological aging during semantic memory retrieval. <h3>Background:</h3> Semantic memory remains relatively stable with normal cognitive aging and its decline might be an indicator of a neurodegenerative disease. Studying EEG correlates of semantic retrieval could provide early markers of neurodegeneration. <h3>Design/Methods:</h3> Twenty-nine young adults (YA: 21.3 years), 22 healthy aging adults (HA: 63.9 years), and 20 patients with mild cognitive impairment (MCI: 67.8 years) participated. We recorded EEG while one completed a semantic task in which one was asked to judge whether two words led to retrieval of an object (retrieval, R) or not (non-retrieval, NR). Using Morlet wavelet time-frequency decomposition, event-related power changes within theta (4–8Hz), alpha (8–12Hz), low-beta (12–20 Hz), and high-beta (20–30 Hz) EEG frequency bands were measured. Power data contrasting R vs NR trials were analyzed separately to compare (1) YA versus HA (normal aging effects) and (2) HA versus MCI (pathological aging effects) using independent t-tests (permutations N = 2000; significance level at FDR of 0.05). <h3>Results:</h3> For normal aging effects, though no behavioral differences between the normal groups, we found theta (NR &gt; R, 628–701 ms) and alpha (R &lt; NR, 555–591 ms) power differences only in YA, and a high-beta power difference (NR &gt; R, 444–481 ms) only in HA. For pathological aging effects, accuracy was reduced in MCI. Two EEG differences were found: a different pattern of high-beta power differences (224–261 ms) in MCI (NR &gt; R) than HA (R &gt; NR), and a low-beta power difference (R &gt; NR, 444–481 ms) only in HA. <h3>Conclusions:</h3> Brain responses transition from slower (alpha, theta) to faster (beta) activity with aging during semantic memory retrieval. Retrieval accuracy declines and patterns of neural oscillation change with MCI. The findings have implications for early detection of pathological aging. <b>Disclosure:</b> The institution of Dr. Chiang has received research support from NIH/NIDCD. The institution of Dr. Chiang has received research support from Texas Alzheimer’s Research and Care Consortium. Ms. Lydon has nothing to disclose. The institution of Dr. Hart has received research support from Department of Defense. Dr. Kraut has nothing to disclose. Raksha Mudar has nothing to disclose.

Heart rate, orthostatic test as markers of pathological aging

Heart rate, orthostatic test as markers of pathological aging

The emerging role of lysine succinylation in ovarian aging

BackgroundOvarian aging is a process of decline in its reserve leading to ovary dysfunction and even reduced health quality in offspring. However, aging-related molecular pathways in the ovary remain obscure. Lysine succinylation (Ksuc), a newly post-translational modification (PTM), has been found to be broadly conserved in both eukaryotic and prokaryotic cells, and associated with multiple pathophysiological processes. There are no relevant reports revealing a link between the molecular mechanisms of ovarian aging and Ksuc.MethodsThe level of Ksuc in ovaries of aged and premature ovarian insufficiency (POI) mice were detected by immunoblotting and immunohistochemical. To further explore the role of Ksuc in ovarian aging, using in vitro mouse ovary tissue culture and an in vivo mouse model with changed Ksuc level.ResultsIncreased Ksuc in ovaries of aged and POI mice and distribution of Ksuc in various types of mice ovarian cells and the high level of Ksuc in granulosa cells (GCs) were revealed. Histological assessments and hormone levels analyses showed that the high Ksuc level down-regulated the ovarian index and the anti-Müllerian hormone (AMH) and estrogen levels, and increased follicular atresia. Moreover, in the high Ksuc groups, the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) intensities and the expression of Cleaved-caspase-3 increased and the expression of B-cell lymphoma-2 (Bcl-2) decreased together with positively-expressed P21, an aging-related marker. These results suggest that ovarian aging is likely associated with alteration in Ksuc.ConclusionThe present study has identified Ksuc in mouse ovary and found that high Ksuc level most likely contributes to ovarian aging which is expected further investigation to provide new information for delaying physiological ovarian aging and treating pathological ovarian aging.

Hippocampal metabolic subregions and networks: Behavioral, molecular, and pathological aging profiles.

Hippocampal local and network dysfunction is the hallmark of Alzheimer's disease (AD). We characterized the spatial patterns of hippocampus differentiation based on brain co-metabolism in healthy elderly participants and demonstrated their relevance to study local metabolic changes and associated dysfunction in pathological aging. The hippocampus can be differentiated into anterior/posterior and dorsal cornu ammonis (CA)/ventral (subiculum) subregions. While anterior/posterior CA show co-metabolism with different regions of the subcortical limbic networks, the anterior/posterior subiculum are parts of cortical networks supporting object-centered memory and higher cognitive demands, respectively. Both networks show relationships with the spatial patterns of gene expression pertaining to cell energy metabolism and AD's process. Finally, while local metabolism is generally lower in posterior regions, the anterior-posterior imbalance is maximal in late mild cognitive impairment with the anterior subiculum being relatively preserved. Future studies should consider bidimensional hippocampal differentiation and in particular the posterior subicular region to better understand pathological aging.

Visual-somatosensory integration (VSI) as a novel marker of Alzheimer's disease: A comprehensive overview of the VSI study.

Identification of novel, non-invasive, non-cognitive based markers of Alzheimer's disease (AD) and related dementias are a global priority. Growing evidence suggests that Alzheimer's pathology manifests in sensory association areas well before appearing in neural regions involved in higher-order cognitive functions, such as memory. Previous investigations have not comprehensively examined the interplay of sensory, cognitive, and motor dysfunction with relation to AD progression. The ability to successfully integrate multisensory information across multiple sensory modalities is a vital aspect of everyday functioning and mobility. Our research suggests that multisensory integration, specifically visual-somatosensory integration (VSI), could be used as a novel marker for preclinical AD given previously reported associations with important motor (balance, gait, and falls) and cognitive (attention) outcomes in aging. While the adverse effect of dementia and cognitive impairment on the relationship between multisensory functioning and motor outcomes has been highlighted, the underlying functional and neuroanatomical networks are still unknown. In what follows we detail the protocol for our study, named The VSI Study, which is strategically designed to determine whether preclinical AD is associated with neural disruptions in subcortical and cortical areas that concurrently modulate multisensory, cognitive, and motor functions resulting in mobility decline. In this longitudinal observational study, a total of 208 community-dwelling older adults with and without preclinical AD will be recruited and monitored yearly. Our experimental design affords assessment of multisensory integration as a new behavioral marker for preclinical AD; identification of functional neural networks involved in the intersection of sensory, motor, and cognitive functioning; and determination of the impact of early AD on future mobility declines, including incident falls. Results of The VSI Study will guide future development of innovative multisensory-based interventions aimed at preventing disability and optimizing independence in pathological aging.

"Just old age" - a qualitative investigation of owner and veterinary professional experiences of and attitudes to ageing in dogs in the UK.

Many UK dogs live into old age, but owners may not recognise or report age-associated signs of disease which lead to negative welfare. This study investigated dog owner and veterinary professional experiences and attitudes towards ageing in dogs, how health care is offered, barriers to its delivery, and some best-practice solutions. In-depth semi-structured interviews were conducted with 15 owners of 21 dogs (aged 8 to 17 years mean: 13) and 11 veterinary professional (eight veterinary surgeons, two nurses and one physiotherapist). Open-text responses from 61 dog owners were collected using an online survey. Transcripts and survey responses were inductively coded into themes. Four themes were constructed: "just old age", barriers to care, trust in veterinary surgeons, and tools to improve health care. Age-related changes were mostly perceived as "just old age" by dog owners. Many dogs were no longer vaccinated and did not attend check-ups unless owners identified a problem. The greatest barriers to health care were finances (dog owners), owner awareness, willingness to act and consultation time (veterinary professionals). Trust in veterinary professionals was more likely when dog owner experienced continuity, prioritisation of care, clear communication and an accessible, knowledgeable and empathic veterinary professional. Participants suggested that senior health care and communication between dog owners and veterinary professionals could be improved through questionnaires, and evidence-based online information. Opportunities to educate owners on which clinical signs represent healthy or pathological ageing are being missed. Resources should be developed to guide on best-practice discussions in consultations, encourage more owners to recognise clinical signs and to seek and trust veterinary advice.

Natural language processing techniques for studying language in pathological ageing: A scoping review.

In the past few years there has been a growing interest in the employment of verbal productions as digital biomarkers, namely objective, quantifiable behavioural data that can be collected and measured by means of digital devices, allowing for a low-cost pathology detection, classification and monitoring. Numerous research papers have been published on the automatic detection of subtle verbal alteration, starting from written texts, raw speech recordings and transcripts, and such linguistic analysis has been singled out as a cost-effective method for diagnosing dementia and other medical conditions common among elderly patients (e.g., cognitive dysfunctions associated with metabolic disorders, dysarthria). To provide a critical appraisal and synthesis of evidence concerning the application of natural language processing (NLP) techniques for clinical purposes in the geriatric population. In particular, we discuss the state of the art on studying language in healthy and pathological ageing, focusing on the latest research efforts to build non-intrusive language-based tools for the early identification of cognitive frailty due to dementia. We also discuss some challenges and open problems raised by this approach. We performed a scoping review to examine emerging evidence about this novel domain. Potentially relevant studies published up to November 2021 were identified from the databases of MEDLINE, Cochrane and Web of Science. We also browsed the proceedings of leading international conferences (e.g., ACL, COLING, Interspeech, LREC) from 2017 to 2021, and checked the reference lists of relevant studies and reviews. The paper provides an introductory, but complete, overview of the application of NLP techniques for studying language disruption due to dementia. We also suggest that this technique can be fruitfully applied to other medical conditions (e.g., cognitive dysfunctions associated with dysarthria, cerebrovascular disease and mood disorders). Despite several critical points need to be addressed by the scientific community, a growing body of empirical evidence shows that NLP techniques can represent a promising tool for studying language changes in pathological aging, with a high potential to lead a significant shift in clinical practice. What is already known on this subject Speech and languages abilities change due to non-pathological neurocognitive ageing and neurodegenerative processes. These subtle verbal modifications can be measured through NLP techniques and used as biomarkers for screening/diagnostic purposes in the geriatric population (i.e., digital linguistic biomarkers-DLBs). What this paper adds to existing knowledge The review shows that DLBs can represent a promising clinical tool, with a high potential to spark a major shift to dementia assessment in the elderly. Some challenges and open problems are also discussed. What are the potential or actual clinical implications of this work? This methodological review represents a starting point for clinicians approaching the DLB research field for studying language in healthy and pathological ageing. It summarizes the state of the art and future research directions of this novel approach.

New Senolysis Approach via Antibody–Drug Conjugate Targeting of the Senescent Cell Marker Apolipoprotein D for Skin Rejuvenation

Senescent cells accumulate in aging skin, causing age-related changes and a decline in functional efficiency. Therefore, senolysis, a treatment that specifically removes senescent cells and rejuvenates the skin, should be explored. We targeted apolipoprotein D (ApoD), a previously identified marker expressed on senescent dermal fibroblasts, and investigated a novel senolysis approach using a monoclonal antibody against this antigen and a secondary antibody conjugated with the cytotoxic drug pyrrolobenzodiazepine. Observations using fluorescently labeled antibodies revealed that ApoD functions as a surface marker of senescent cells and that the antibody is taken up and internalized only by such cells. The concurrent administration of the antibody with the PBD-conjugated secondary antibody specifically eliminated only senescent cells without harming young cells. The antibody-drug conjugate treatment of aging mice combined with the administration of antibodies reduced the number of senescent cells in the dermis of mice and improved the senescent skin phenotype. These results provide a proof-of-principle evaluation of a novel approach to specifically eliminate senescent cells using antibody-drug conjugates against senescent cell marker proteins. This approach is a potential candidate for clinical applications to treat pathological skin aging and related diseases via the removal of senescent cells.

Olfaction and Anxiety Are Differently Associated in Men and Women in Cognitive Physiological and Pathological Aging

Olfaction impairment in aging is associated with increased anxiety. We explored this association in cognitively healthy controls (HCs), Mild Cognitive Impairment (MCI) and Parkinson's disease (PD) patients. Both olfaction and anxiety have sex differences, therefore we also investigated these variances. Investigate the association of olfaction with anxiety in three distinct clinical categories of aging, exploring the potential role of sex. 117 subjects (29 HCs, 43 MCI, and 45 PD patients) were assessed for olfaction and anxiety. We used regression models to determine whether B-SIT predicted anxiety and whether sex impacted that relationship. Lower olfaction was related to greater anxiety traits in all groups (HCs: p = 0.015; MCI: p = 0.001 and PD: p = 0.038), significantly differed by sex. In fact, in HCs, for every unit increase in B-SIT, anxiety traits decreased by 7.63 in men (p = 0.009) and 1.5 in women (p = 0.225). In MCI patients for every unit increase in B-SIT, anxiety traits decreased by 1.19 in men (p = 0.048) and 3.03 in women (p = 0.0036). Finally, in PD patients for every unit increase in B-SIT, anxiety traits decreased by 1.73 in men (p = 0.004) and 0.41 in women (p = 0.3632). Olfaction and anxiety are correlated in all three distinct diagnostic categories, but differently in men and women.

Encoding of everyday objects in older adults: Episodic memory assessment in virtual reality.

Age-related decline in episodic memory performance in otherwise healthy older adults is indisputably evident. Yet, it has been shown that under certain conditions episodic memory performance in healthy older adults' barely deviates from those seen in young adults. Here we report on the quality of object encoding in an ecologically valid, virtual-reality based memory assessment in a sample of healthy older and younger adults with comparable memory performance. We analyzed encoding by establishing both a serial and semantic clustering index and an object memory association network. As expected, semantic clustering was superior in older adults without need for additional allocation of executive resources whereas young adults tended more to rely on serial strategies. The association networks suggested a plethora of obvious but also less obvious memory organization principles, some of which indicated converging approaches between the groups as suggested by a subgraph analysis and some of which indicated diverging approaches as suggested by the respective network interconnectivity. A higher interconnectivity was observed in the older adults' association networks. We interpreted this as a consequence of superior semantic memory organization (extent to which effective semantic strategies diverged within the group). In conclusion, these results might indicate a diminished need for compensatory cognitive effort in healthy older adults when encoding and recalling everyday objects under ecologically valid conditions. Due to an enhanced and multimodal encoding model, superior crystallized abilities might be sufficient to counteract an age-related decline in various other and specific cognitive domains. This approach might potentially elucidate age-related changes in memory performance in both healthy and pathological aging.