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Article ; Online: Repurposing Erectile Dysfunction Medication for Alzheimer Disease Prevention.

Yasar, Sevil / Nidadavolu, Lolita

2024 Volume 102, Issue 4, Page(s) e209180

MeSH term(s)	Male ; Humans ; Erectile Dysfunction/drug therapy ; Erectile Dysfunction/prevention & control ; Alzheimer Disease/drug therapy ; Alzheimer Disease/prevention & control ; Risk Factors
Language	English
Publishing date	2024-02-07
Publishing country	United States
Document type	Editorial
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000209180
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Article ; Online: Underlying Vulnerabilities to the Cytokine Storm and Adverse COVID-19 Outcomes in the Aging Immune System.

Nidadavolu, Lolita S / Walston, Jeremy D

The journals of gerontology. Series A, Biological sciences and medical sciences

2020 Volume 76, Issue 3, Page(s) e13–e18

Abstract: Older adults are far more vulnerable to adverse health outcomes and mortality after contracting COVID-19. There are likely multiple age-related biological, clinical, and environmental reasons for this increased risk, all of which are exacerbated by ... ...

Abstract	Older adults are far more vulnerable to adverse health outcomes and mortality after contracting COVID-19. There are likely multiple age-related biological, clinical, and environmental reasons for this increased risk, all of which are exacerbated by underlying age-associated changes to the immune system as well as increased prevalence of chronic disease states in older adults. Innate immune system overactivity, termed the cytokine storm, appears to be critical in the development of the worst consequences of COVID-19 infection. Pathophysiology suggests that viral stimulation of the innate immune system, augmented by inflammatory signals sent from dying cells, ramps up into a poorly controlled outpouring of inflammatory mediators. Other aging-related changes in cells such as senescence as well as higher prevalence of chronic disease states also likely ramp up inflammatory signaling. This in turn drives downstream pathophysiological changes to pulmonary, cardiovascular, skeletal muscle, and brain tissues that drive many of the adverse health outcomes observed in older adults. This article provides an overview of the underlying etiologies of innate immune system activation and adaptive immune system dysregulation in older adults and how they potentiate the consequences of the COVID-19-related cytokine storm, and possible uses of this knowledge to develop better risk assessment and treatment monitoring strategies.
MeSH term(s)	Age Factors ; Aged ; Aging/immunology ; COVID-19/immunology ; COVID-19/physiopathology ; Cellular Senescence/immunology ; Cytokine Release Syndrome/virology ; Cytokines/immunology ; Humans ; Immunity, Innate ; Pneumonia, Viral/immunology ; Pneumonia, Viral/physiopathology ; SARS-CoV-2 ; Signal Transduction
Chemical Substances	Cytokines
Keywords	covid19
Language	English
Publishing date	2020-08-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1223643-3
ISSN	1758-535X ; 1079-5006
ISSN (online)	1758-535X
ISSN	1079-5006
DOI	10.1093/gerona/glaa209
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Article ; Online: Underlying Vulnerabilities to the Cytokine Storm and Adverse COVID-19 Outcomes in the Aging Immune System

Nidadavolu, Lolita S / Walston, Jeremy D

The Journals of Gerontology: Series A ; ISSN 1079-5006 1758-535X

2020

Abstract: Abstract Older adults are far more vulnerable to adverse health outcomes and mortality after contracting COVID-19. There are likely multiple age-related biological, clinical, and environmental reasons for this increased risk, all of which are exacerbated ...

Abstract	Abstract Older adults are far more vulnerable to adverse health outcomes and mortality after contracting COVID-19. There are likely multiple age-related biological, clinical, and environmental reasons for this increased risk, all of which are exacerbated by underlying age-associated changes to the immune system as well as increased prevalence of chronic disease states in older adults. Innate immune system overactivity, termed the cytokine storm, appears to be critical in the development of the worst consequences of COVID-19 infection. Pathophysiology suggests that viral stimulation of the innate immune system, augmented by inflammatory signals sent from dying cells, ramps up into a poorly controlled outpouring of inflammatory mediators. Other aging-related changes in cells such as senescence as well as higher prevalence of chronic disease states also likely ramp up inflammatory signaling. This in turn drives downstream pathophysiological changes to pulmonary, cardiovascular, skeletal muscle, and brain tissues that drive many of the adverse health outcomes observed in older adults. This article provides an overview of the underlying etiologies of innate immune system activation and adaptive immune system dysregulation in older adults and how they potentiate the consequences of the COVID-19-related cytokine storm, and possible uses of this knowledge to develop better risk assessment and treatment monitoring strategies.
Keywords	Ageing ; Geriatrics and Gerontology ; covid19
Language	English
Publisher	Oxford University Press (OUP)
Publishing country	uk
Document type	Article ; Online
DOI	10.1093/gerona/glaa209
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Article ; Online: Preoperative Evaluation of the Frail Patient.

Nidadavolu, Lolita S / Ehrlich, April L / Sieber, Frederick E / Oh, Esther S

Anesthesia and analgesia

2020 Volume 130, Issue 6, Page(s) 1493–1503

Abstract: Perioperative management of older adults is a complex field that is heavily influenced by the clinical heterogeneity of older adults. Frailty-a geriatric syndrome in which a patient is more vulnerable to stressors due to decreases in physical function ... ...

Abstract	Perioperative management of older adults is a complex field that is heavily influenced by the clinical heterogeneity of older adults. Frailty-a geriatric syndrome in which a patient is more vulnerable to stressors due to decreases in physical function and reserve-has been indicative of adverse postoperative outcomes. Many tools have been developed to measure frailty that incorporate a variety of factors including physical and cognitive function, comorbidities, self-reported measures of health, and clinical judgment. Most of these frailty assessment tools are able to identify a subset of patients at risk of adverse outcomes including postoperative complications, longer hospital length of stay, discharge to a higher level of care, and mortality. Frailty assessment before surgical interventions can also guide discussions among patients, their families, anesthesiologists, and surgeons to tailor operative plans for patients to mitigate this increased risk. Studies are ongoing to identify interventions in frail patients that can improve postoperative outcomes, but high-quality data in the form of randomized controlled trials are lacking at this time.
MeSH term(s)	Aged ; Cognition Disorders ; Frail Elderly ; Frailty/surgery ; Geriatric Assessment/methods ; Humans ; Length of Stay ; Patient Discharge ; Postoperative Complications/prevention & control ; Preoperative Care/methods ; Risk Assessment ; Risk Factors ; United States
Language	English
Publishing date	2020-05-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	80032-6
ISSN	1526-7598 ; 0003-2999
ISSN (online)	1526-7598
ISSN	0003-2999
DOI	10.1213/ANE.0000000000004735
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Article ; Online: Valsartan and sacubitril combination treatment enhances collagen production in older adult human skin cells.

Marin, Sela / Godet, Inês / Nidadavolu, Lolita S / Tian, Jing / Dickinson, Laura E / Walston, Jeremy D / Gilkes, Daniele M / Abadir, Peter M

Experimental gerontology

2022 Volume 165, Page(s) 111835

Abstract: Collagen is a major component of the skin's support system, allowing for its firmness, elasticity, and mechanical strength. Skin collagen production decreases as we age and is associated with increased sagging, wrinkling, and thinning. The Renin- ... ...

Abstract	Collagen is a major component of the skin's support system, allowing for its firmness, elasticity, and mechanical strength. Skin collagen production decreases as we age and is associated with increased sagging, wrinkling, and thinning. The Renin-Angiotensin System (RAS) is a key hormonal system that changes with age and affects multiple organ systems. The primary health benefits of Angiotensin (Ang) receptor type1 (AT
MeSH term(s)	Aged ; Aminobutyrates/pharmacology ; Aminobutyrates/therapeutic use ; Angiotensin Receptor Antagonists/pharmacology ; Angiotensin Receptor Antagonists/therapeutic use ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Biphenyl Compounds/pharmacology ; Biphenyl Compounds/therapeutic use ; Collagen ; Drug Combinations ; Heart Failure/metabolism ; Humans ; Neprilysin/pharmacology ; Neprilysin/therapeutic use ; Stroke Volume/physiology ; Tetrazoles/pharmacology ; Treatment Outcome ; Valsartan/pharmacology ; Valsartan/therapeutic use
Chemical Substances	Aminobutyrates ; Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Biphenyl Compounds ; Drug Combinations ; Tetrazoles ; sacubitril (17ERJ0MKGI) ; Valsartan (80M03YXJ7I) ; Collagen (9007-34-5) ; Neprilysin (EC 3.4.24.11)
Language	English
Publishing date	2022-05-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	390992-x
ISSN	1873-6815 ; 0531-5565
ISSN (online)	1873-6815
ISSN	0531-5565
DOI	10.1016/j.exger.2022.111835
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Article: Associations between circulating cell-free mitochondrial DNA, inflammatory markers, and cognitive and physical outcomes in community dwelling older adults.

Nidadavolu, Lolita S / Feger, Danielle / Chen, Diefei / Wu, Yuqiong / Grodstein, Francine / Gross, Alden L / Bennett, David A / Walston, Jeremy D / Oh, Esther S / Abadir, Peter M

Immunity & ageing : I & A

2023 Volume 20, Issue 1, Page(s) 24

Abstract: Background: Dementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. ... ...

Abstract	Background: Dementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has been proposed as an immune stimulator and potential predictor of mortality in acute illnesses. Dementia and frailty are both associated with mitochondrial dysfunction, impaired cellular energetics, and cell death. The size and abundance of ccf-mtDNA fragments may indicate the mechanism of cell death: long fragments typically result from necrosis, while short fragments arise from apoptosis. We hypothesize that increased levels of necrosis-associated long ccf-mtDNA fragments and inflammatory markers in serum are linked to declines in cognitive and physical function, as well as increased mortality risk. Results: Our study of 672 community-dwelling older adults revealed that inflammatory markers (C-Reactive Protein, soluble tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 [sTNFR1], and interleukin-6 [IL-6]) positively correlated with ccf-mtDNA levels in serum. Although cross-sectional analysis revealed no significant associations between short and long ccf-mtDNA fragments, longitudinal analysis demonstrated a connection between higher long ccf-mtDNA fragments (necrosis-associated) and worsening composite gait scores over time. Additionally, increased mortality risk was observed only in individuals with elevated sTNFR1 levels. Conclusion: In a community dwelling cohort of older adults, there are cross-sectional and longitudinal associations between ccf-mtDNA and sTNFR1 with impaired physical and cognitive function and increased hazard of death. This work suggests a role for long ccf-mtDNA as a blood-based marker predictive of future physical decline.
Language	English
Publishing date	2023-05-23
Publishing country	England
Document type	Journal Article
ZDB-ID	2168941-6
ISSN	1742-4933
ISSN	1742-4933
DOI	10.1186/s12979-023-00342-y
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Article ; Online: Angiotensin receptor blocker use is associated with upregulation of the memory-protective angiotensin type 4 receptor (AT

Cosarderelioglu, Caglar / Nidadavolu, Lolita S / George, Claudene J / Marx-Rattner, Ruth / Powell, Laura / Xue, Qian-Li / Tian, Jing / Oh, Esther S / Ferrucci, Luigi / Dincer, Pervin / Bennett, David A / Walston, Jeremy D / Abadir, Peter M

GeroScience

2022 Volume 45, Issue 1, Page(s) 371–384

Abstract: The reported primary dementia-protective benefits of angiotensin II type 1 receptor ( ... ...

Abstract	The reported primary dementia-protective benefits of angiotensin II type 1 receptor (AT
MeSH term(s)	Humans ; Aged ; Aged, 80 and over ; Angiotensin Receptor Antagonists/pharmacology ; Angiotensin Receptor Antagonists/therapeutic use ; Up-Regulation ; Angiotensin-Converting Enzyme Inhibitors ; Brain/metabolism ; Alzheimer Disease/drug therapy ; Alzheimer Disease/complications ; Amyloid beta-Peptides/metabolism ; Cognitive Dysfunction ; Angiotensins ; Inflammation/complications
Chemical Substances	Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Amyloid beta-Peptides ; Angiotensins
Language	English
Publishing date	2022-08-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2886586-8
ISSN	2509-2723 ; 2509-2715
ISSN (online)	2509-2723
ISSN	2509-2715
DOI	10.1007/s11357-022-00639-8
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Article ; Online: Circulating Cell-Free Genomic DNA Is Associated with an Increased Risk of Dementia and with Change in Cognitive and Physical Function.

Nidadavolu, Lolita S / Feger, Danielle / Wu, Yuqiong / Grodstein, Francine / Gross, Alden L / Bennett, David A / Walston, Jeremy D / Oh, Esther S / Abadir, Peter M

Journal of Alzheimer's disease : JAD

2022 Volume 89, Issue 4, Page(s) 1233–1240

Abstract: Background: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA).: Objective: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) ...

Abstract	Background: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA). Objective: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults. Methods: We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education. Results: Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up. Conclusion: This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty.
MeSH term(s)	Aged ; Cell-Free Nucleic Acids ; Cognition/physiology ; Cognitive Dysfunction/epidemiology ; Cognitive Dysfunction/genetics ; Dementia/epidemiology ; Dementia/genetics ; Frailty/psychology ; Genomics ; Humans
Chemical Substances	Cell-Free Nucleic Acids
Language	English
Publishing date	2022-06-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-220301
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Article: Brain Renin-Angiotensin System at the Intersect of Physical and Cognitive Frailty.

Cosarderelioglu, Caglar / Nidadavolu, Lolita S / George, Claudene J / Oh, Esther S / Bennett, David A / Walston, Jeremy D / Abadir, Peter M

Frontiers in neuroscience

2020 Volume 14, Page(s) 586314

Abstract: The renin-angiotensin system (RAS) was initially considered to be part of the endocrine system regulating water and electrolyte balance, systemic vascular resistance, blood pressure, and cardiovascular homeostasis. It was later discovered that intracrine ...

Abstract	The renin-angiotensin system (RAS) was initially considered to be part of the endocrine system regulating water and electrolyte balance, systemic vascular resistance, blood pressure, and cardiovascular homeostasis. It was later discovered that intracrine and local forms of RAS exist in the brain apart from the endocrine RAS. This brain-specific RAS plays essential roles in brain homeostasis by acting mainly through four angiotensin receptor subtypes; AT
Language	English
Publishing date	2020-09-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2020.586314
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Article ; Online: Interleukin-6 Drives Mitochondrial Dysregulation and Accelerates Physical Decline: Insights From an Inducible Humanized IL-6 Knock-In Mouse Model.

The journals of gerontology. Series A, Biological sciences and medical sciences

2023 Volume 78, Issue 10, Page(s) 1740–1752

Abstract: Chronic activation of inflammatory pathways (CI) and mitochondrial dysfunction are independently linked to age-related functional decline and early mortality. Interleukin 6 (IL-6) is among the most consistently elevated chronic activation of inflammatory ...

Abstract	Chronic activation of inflammatory pathways (CI) and mitochondrial dysfunction are independently linked to age-related functional decline and early mortality. Interleukin 6 (IL-6) is among the most consistently elevated chronic activation of inflammatory pathways markers, but whether IL-6 plays a causative role in this mitochondrial dysfunction and physical deterioration remains unclear. To characterize the role of IL-6 in age-related mitochondrial dysregulation and physical decline, we have developed an inducible human IL-6 (hIL-6) knock-in mouse (TetO-hIL-6mitoQC) that also contains a mitochondrial-quality control reporter. Six weeks of hIL-6 induction resulted in upregulation of proinflammatory markers, cell proliferation and metabolic pathways, and dysregulated energy utilization. Decreased grip strength, increased falls off the treadmill, and increased frailty index were also observed. Further characterization of skeletal muscles postinduction revealed an increase in mitophagy, downregulation of mitochondrial biogenesis genes, and an overall decrease in total mitochondrial numbers. This study highlights the contribution of IL-6 to mitochondrial dysregulation and supports a causal role of hIL-6 in physical decline and frailty.
MeSH term(s)	Mice ; Humans ; Animals ; Interleukin-6/genetics ; Interleukin-6/metabolism ; Frailty ; Mitochondria/genetics ; Mitochondria/metabolism ; Disease Models, Animal ; Muscle, Skeletal/metabolism
Chemical Substances	Interleukin-6
Language	English
Publishing date	2023-06-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1223643-3
ISSN	1758-535X ; 1079-5006
ISSN (online)	1758-535X
ISSN	1079-5006
DOI	10.1093/gerona/glad147
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