Daniela Bakula’s research while affiliated with IT University of Copenhagen and other places

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Publications (54)


Fig. 1 Risk exposure levels in low and high altitude regions of Ethiopia. a-d Elevation-based variation in risk exposure levels. e-h Changes in risk exposure levels over 30 years from 1990
Fig. 6 Resting metabolic rate of highland and lowland dwellers and its effect on the rate of aging and senescence. a-g Relationship of resting metabolic rate (RMR) with elevation,
Deep learning reveals diverging effects of altitude on aging
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  • Full-text available

January 2025

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12 Reads

GeroScience

Amanuel Abraha Teklu

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Indra Heckenbach

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Aging is influenced by a complex interplay of multifarious factors, including an individual’s genetics, environment, and lifestyle. Notably, high altitude may impact aging and age-related diseases through exposures such as hypoxia and ultraviolet (UV) radiation. To investigate this, we mined risk exposure data (summary exposure value), disease burden data (disability-adjusted life years (DALYs)), and death rates and life expectancy from the Global Health Data Exchange (GHDx) and National Data Management Center for Health of Ethiopia for each subnational region of Ethiopia, a country with considerable differences in the living altitude. We conducted a cross-sectional clinical trial involving 227 highland and 202 lowland dwellers from the Tigray region in Northern Ethiopia to gain a general insight into the biological aging at high altitudes. Notably, we observed significantly lower risk exposure rates and a reduced disease burden as well as increased life expectancy by lower mortality rates in higher-altitude regions of Ethiopia. When assessing biological aging using facial photographs, we found a faster rate of aging with increasing elevation, likely due to greater UV exposure. Conversely, analysis of nuclear morphologies of peripheral blood mononuclear cells (PBMCs) in blood smears with five different senescence predictors revealed a significant decrease in DNA damage-induced senescence in both monocytes and lymphocytes with increasing elevation. Overall, our findings suggest that disease and DNA damage-induced senescence decreases with altitude in agreement with the idea that oxidative stress may drive aging.

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Figure 1. Timeline of longevity biotechnology. Key breakthroughs in the AI, biomarkers and clocks, geroscience, and clinical trials and applications in ageing and longevity fields since 2013.
Figure 3. Integration of AI, biomarkers and clocks, geroscience, and longevity medicine in advancing human healthspan.
Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity

October 2024

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619 Reads

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5 Citations

Aging

The recent unprecedented progress in ageing research and drug discovery brings together fundamental research and clinical applications to advance the goal of promoting healthy longevity in the human population. We, from the gathering at the Aging Research and Drug Discovery Meeting in 2023, summarised the latest developments in healthspan biotechnology, with a particular emphasis on artificial intelligence (AI), biomarkers and clocks, geroscience, and clinical trials and interventions for healthy longevity. Moreover, we provide an overview of academic research and the biotech industry focused on targeting ageing as the root of age-related diseases to combat multimorbidity and extend healthspan. We propose that the integration of generative AI, cutting-edge biological technology, and longevity medicine is essential for extending the productive and healthy human lifespan.


Figure 1: Risk exposure levels in low and high altitude regions of Ethiopia. a-d Elevation based variation in risk exposure levels. e-h Changes in risk exposure levels over thirty years from 1990 to 2021. i-k Age-specific difference in risk exposure levels. l-n Magnitude of risk exposure levels in males, females or both.
Figure 4. Senescence status of highland and lowland dwellers. a Workflow of senescence prediction from nuclear morphology of PBMCs. b-u Scatter plots of the different models versus indicated parameters of the study participants.
Deep learning reveals diverging effects of altitude on aging

September 2024

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27 Reads

Aging is influenced by a complex interplay of multifarious factors, including an individuals genetics, environment, and lifestyle. Notably, high altitude may impact aging and age-related diseases through exposures such as hypoxia and ultraviolet radiation. To investigate this, we mined summary exposure value as a measure of risk exposure levels, and disability-adjusted life years (DALYs) as a measure of disease burden from the Global Health Data Exchange (GHDx) for each subnational region of Ethiopia, a country with considerable differences in the living altitude. We conducted a cross-sectional clinical trial involving 227 highland and 202 lowland dwellers from the Tigray region in Northern Ethiopia to gain a general insight into the biological aging at high altitudes. Notably, we observed significantly lower risk exposure rates and a reduced disease burden in higher-altitude regions of Ethiopia. When assessing biological aging using facial photographs, we found a faster rate of aging with increasing elevation, likely due to greater UV exposure. Conversely, analysis of nuclear morphologies of peripheral blood mononuclear cells in blood smears (PBMCs) with five different senescence predictors revealed a significant decrease in DNA damage-induced senescence in both monocytes and lymphocytes with increasing elevation. Overall, our findings suggest that disease and DNA damage-induced senescence decreases with altitude increase in agreement with the idea that chronic hypoxic stress may drive aging.


Figure 1. Identification of progeroid syndromes for database. Flow diagram illustrating the process of identifying new progeroid syndromes for mitodb.com including search, inclusion and exclusion criteria.
Figure 2. Progeroid syndrome overview. (A) Agglomerative hierarchical cluster based on phenotype prevalences using uncentered similarity and average linkage. (dark green are new to the database, other colors represent different clusters). Each syndrome group is color coded in the inner circle. (B) Principal component analysis of diseases based on the prevalence of phenotypes. (C) Hierarchical clustering of publicly available dataset for some premature aging diseases and the shared pathways between closely associated diseases. (D) Support vector machine scores for premature aging diseases (available at https://www.mitodb.com).
Figure 3. Hierarchical clusters and syndrome networks. Agglomerative hierarchical clustering and network algorithms of mitochondrial syndromes (A, B), DNA-repair syndromes (C, D) and syndromes with abnormal autophagy (E, F).
Figure 5. Possible progeroid syndromes. (A) A network containing progeroid syndromes and MGORS, (B) network containing progeroid syndromes and SPG49, (C) network containing progeroid syndromes and ATDL2 and (D) a hierarchical cluster with progeroid syndromes, MGORS, ATLD2 and SPG49.
Defining the progeria phenome

February 2024

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52 Reads

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2 Citations

Aging

Progeroid disorders are a heterogenous group of rare and complex hereditary syndromes presenting with pleiotropic phenotypes associated with normal aging. Due to the large variation in clinical presentation the diseases pose a diagnostic challenge for clinicians which consequently restricts medical research. To accommodate the challenge, we compiled a list of known progeroid syndromes and calculated the mean prevalence of their associated phenotypes, defining what we term the 'progeria phenome'. The data were used to train a support vector machine that is available at https://www.mitodb.com and able to classify progerias based on phenotypes. Furthermore, this allowed us to investigate the correlation of progeroid syndromes and syndromes with various pathogenesis using hierarchical clustering algorithms and disease networks. We detected that ataxia-telangiectasia like disorder 2, spastic paraplegia 49 and Meier-Gorlin syndrome display strong association to progeroid syndromes, thereby implying that the syndromes are previously unrecognized progerias. In conclusion, our study has provided tools to evaluate the likelihood of a syndrome or patient being progeroid. This is a considerable step forward in our understanding of what constitutes a premature aging disorder and how to diagnose them.



The human pathome shows sex and tissue specific aging patterns

March 2023

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120 Reads

Little is known about tissue specific changes that occur with aging in humans. Using the description of 33 million histological samples we extract thousands of age- and mortality-associated features from text narratives that we call The Human Pathome (pathoage.com). Notably, we can determine when pathological aging starts at the organism and tissue level, indicating a sexual dimorphism with females aging earlier but slower and males aging later but faster. We employ unsupervised topic-modelling to identify terms and themes that predict age and mortality. As a proof of principle, we cross reference these terms in PubMed to identify nintedanib as a potential aging intervention and show that nintedanib reduces markers of cellular senescence, reduces pro-fibrotic gene pathways in senescent cells and extends the lifespan of fruit flies. Our findings pave the way for expanded exploitation of population datasets towards discovery of novel aging interventions.


The human pathome shows sex specific aging patterns post-development

February 2023

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64 Reads

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2 Citations

Little is known about tissue specific changes that occur with aging in humans. Using the description of 33 million histological samples we extract thousands of age- and mortality-associated features from text narratives that we call The Human Pathome (pathoage.com). Notably, we can broadly determine when pathological aging starts, indicating a sexual dimorphism with females aging earlier but slower and males aging later but faster. Using machine learning, we employ unsupervised topic-modelling to identify terms and themes that predict age and mortality. As a proof of principle, we cross reference these terms in PubMed to identify nintedanib as a potential aging intervention and show that nintedanib reduces markers of cellular senescence, reduces pro-fibrotic gene pathways in senescent cells and extends the lifespan of fruit flies. Our findings pave the way for expanded exploitation of population datasets towards discovery of novel aging interventions.


Nuclear morphology is a deep learning biomarker of cellular senescence

August 2022

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305 Reads

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118 Citations

Nature Aging

Cellular senescence is an important factor in aging and many age-related diseases, but understanding its role in health is challenging due to the lack of exclusive or universal markers. Using neural networks, we predict senescence from the nuclear morphology of human fibroblasts with up to 95% accuracy, and investigate murine astrocytes, murine neurons, and fibroblasts with premature aging in culture. After generalizing our approach, the predictor recognizes higher rates of senescence in p21-positive and ethynyl-2’-deoxyuridine (EdU)-negative nuclei in tissues and shows an increasing rate of senescent cells with age in H&E-stained murine liver tissue and human dermal biopsies. Evaluating medical records reveals that higher rates of senescent cells correspond to decreased rates of malignant neoplasms and increased rates of osteoporosis, osteoarthritis, hypertension and cerebral infarction. In sum, we show that morphological alterations of the nucleus can serve as a deep learning predictor of senescence that is applicable across tissues and species and is associated with health outcomes in humans.


Ketones facilitate transcriptional resolution of secondary DNA structures in premature aging

March 2022

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83 Reads

There is currently no established intervention for Cockayne syndrome, a disease characterized by progressive early onset neurodegeneration with features of premature aging. Here, we tested if acetyl-CoA precursors, citrate and beta-hydroxybutyrate, could reduce features of Cockayne syndrome in three model systems. We identified the gene Helicase 89B as a homologue of CSB in drosophila and found that the ketone beta-hydroxybutyrate rescued features of premature aging in Hel89B deficient flies. In mammals, loss of the citrate carrier Indy exacerbated the phenotype of Csb m/m mice which was rescued by a ketogenic diet. The rescue effect appeared to be mediated through ketone stimulated histone acetylation and facilitation of transcriptional readthrough of secondary DNA structures. These findings link a ketogenic diet with transcriptional resolution of secondary structures and DNA repair.


FIGURE 1 | Biomarkers for clinical trials targeting aging. The effectiveness of interventions can be evaluated by using a combination of biomarkers. In the last years, different biomarkers have been proposed using various sample-and measurement-types.
List of clinical trials targeting aging.
Clinical Trials Targeting Aging

February 2022

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159 Reads

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39 Citations

Frontiers in Aging

The risk of morbidity and mortality increases exponentially with age. Chronic inflammation, accumulation of DNA damage, dysfunctional mitochondria, and increased senescent cell load are factors contributing to this. Mechanistic investigations have revealed specific pathways and processes which, proposedly, cause age-related phenotypes such as frailty, reduced physical resilience, and multi-morbidity. Among promising treatments alleviating the consequences of aging are caloric restriction and pharmacologically targeting longevity pathways such as the mechanistic target of rapamycin (mTOR), sirtuins, and anti-apoptotic pathways in senescent cells. Regulation of these pathways and processes has revealed significant health- and lifespan extending results in animal models. Nevertheless, it remains unclear if similar results translate to humans. A requirement of translation are the development of age- and morbidity associated biomarkers as longitudinal trials are difficult and not feasible, practical, nor ethical when human life span is the endpoint. Current biomarkers and the results of anti-aging intervention studies in humans will be covered within this paper. The future of clinical trials targeting aging may be phase 2 and 3 studies with larger populations if safety and tolerability of investigated medication continues not to be a hurdle for further investigations.


Citations (26)


... AGING scope to biological age estimation [12], and Wang et al. (2023) discussed biomarkers and aging clocks [13]; however, neither provided a comprehensive analysis centered on GenAI and DL. Steurer et al. (2024) offered an overview of multimodal transformers-a type of GenAI-in aging research [14], while Lyu et al. (2024) extended the scope of their publication vastly beyond DL and GenAI [15]. Although presented an in-depth analysis of DL in aging research [16], the rapid advancements in AI techniques since then necessitate an updated review. ...

Reference:

Deep learning and generative artificial intelligence in aging research and healthy longevity medicine
Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity

Aging

... Morten Scheibye-Knudsen, University of Copenhagen, Denmark, addressed the limited understanding of age-related tissue changes in humans (62). Utilizing a vast dataset of 33 million histological samples, he and colleagues have extracted numerous age-and mortality-related features from textual descriptions, referred to as The Human Pathome (pathoage.com). ...

The human pathome shows sex specific aging patterns post-development
  • Citing Preprint
  • February 2023

... We propose that other cellular hallmarks like nuclear morphology be thoroughly investigated to determine whether they are characteristic of both aging and the pathology of IPF. For instance, age-related nuclear architectural changes encompass alterations in morphology, telomere shortening, heterochromatin loss, and changes in the composition and structure of the nuclear envelope [200]. Therefore, studying nuclear architecture represents a significant research and drug development opportunity. ...

Nuclear morphology is a deep learning biomarker of cellular senescence

Nature Aging

... A study assessing geroprotective effects, and using mortality as primary endpoint, would have to run over several decades in order to determine whether the treatment is effective. The vast resources required to complete such a trial currently prevent CGPIs from entering phase II or III testing in humans [7]. ...

Clinical Trials Targeting Aging

Frontiers in Aging

... CNOT6 possesses 3 ′ -5 ′ RNase activity on polyadenylated RNA substrates and is a catalytic subunit of the CCR4-NOT complex, which is involved in the regulation of mRNA degradation, translation, and transcription [41]. Although CNOT6 depletion appears to have a relatively minor impact on mRNA metabolism due to the compensatory role of its paralog CNOT6L, CNOT6 repression can still result in increased stability of certain mRNAs [42]. ...

CNOT6: A Novel Regulator of DNA Mismatch Repair

Cells

... Towards this end, animal models have been used to screen for compounds that extend the lifespan [87]. Pharmaceutical corporations and venture capitals have invested heavily in projects targeting hallmarks of aging and to extend the lifespan [88][89][90], and some promising drug candidates are already in clinical trials. ...

Meeting Report: Aging Research and Drug Discovery

Aging

... An innate biological process that is adaptable and responsive to therapeutic interventions coexists with aging. Using of various genetic, nutritional, and pharmaceutical interventions, scientists have made impressive strides in the last few decades in extending the lifespan (Mkrtchyan et al., 2020;Sourada and Kuglík, 2020;Wang et al., 2022). Therefore, it is crucial to identify biomarkers that influence the aging process and associated health risks, given the growing severity of the global population aging issue. ...

ARDD 2020: from aging mechanisms to interventions

Aging

... 13 State-of-the-art in current image analysis for age prediction includes artificial intelligence (AI)-based algorithms including CNNs. 1,2 These methods give an opportunity to the fast analysis of large datasets with a satisfactory accuracy. [14][15][16][17][18][19] Moreover, they help to discover new age-related features, such as eye corners 20 or facial wrinkles. ...

Latest advances in aging research and drug discovery
  • Citing Article
  • November 2019

... This approach aligns with recent human studies, which point to molecular damage as a key factor in age-related phenotypes (25). Furthermore, the shorter lifespan of laboratory animals allows for accelerated investigation into aging, offering valuable insights into mitigating molecular damage and developing interventions that can slow aging processes (26). Ensuring the standardization of aging, as a physiological process, in experimental studies will significantly contribute to research in the field of gerontology. ...

New methodologies in ageing research

Ageing Research Reviews

... This decline is linked to altered ATP production and an increase in the generation of reactive oxygen species (ROS) [65]. Excessive ROS can lead to the oxidation of mitochondrial DNA, proteins, and lipids, impairing the cell's ability to activate mitophagy and ultimately resulting in mitochondrial dysfunction [66,67]. ...

MitophAging: Mitophagy in Aging and Disease