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Neurodegeneration: Effects of calorie restriction on the brain sirtuin protein levels
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Introduction
Neurodegenerative
diseases (NDDs) pose substantial health challenges, causing severe
morbidity and disabilities that can impact a significant portion of the
population [1], [2], [3], [4]. Currently, dementia affects 36.5 million
individuals globally, with 5–7 million new cases of Alzheimer's Disease
(AD) recorded each year [2], [5]. Census data predicts 13.8 million AD
patients in the USA by 2050 [6]. Multiple factors within human
populations affect the impact of disorders and mortality. Giannouli
underscores the critical roles that family bonds and
religiosity–spirituality may play in treatment maintenance, adherence,
and outcomes [7]. These elements also enhance disease resistance through
social support, reduced exposure to environmental risk factors, and
improved management of comorbid medical conditions that could lead to
death. However, limited information in medical records and challenges in
conducting new prospective studies pose significant restrictions.
Sirtuin
Proteins (SIRT) constitute a crucial group of proteins involved in gene
silencing, genomic stability, cellular longevity, and metabolic
regulation through the deacetylation of histones. Comprising seven
well-conserved protein complexes, sirtuins play a vital role in aging,
apoptosis, and neurodegenerative diseases by regulating cellular
stability [8], [9], [10]. They are instrumental in remodeling chromatin,
influencing cellular mechanisms, and modulating gene expression.
Numerous studies, employing various animal models, have underscored the
involvement of SIRT in neurological diseases [8], [11], [12], [13],
[14], [15], [16].
In this
context, research has demonstrated that overexpression of SIRT1
protects neurons from toxicity induced by mutated superoxide dismutase 1
in both neuron cultures and mouse brains [17], [18]. Conversely,
deficiencies in SIRT have been shown to exacerbate neurodegenerative
disorders in lethal neurological diseases [19]. SIRT1 and SIRT3 emerge
as key players in neuronal functions, particularly influencing synaptic
plasticity and memory formation [20]. Their regulatory roles in the
brain's essential functions position them as potential contributors to
the pathogenesis of various neurodegenerative disorders [21].
The
significance of both SIRT1 and SIRT6 stems from their regulatory
effects on NF-κB. NF-κB governs genes involved in apoptosis, cell aging,
inflammation, and immunity, with its activity increasing with age in
many mammalian tissues and stem cells [22]. In the central nervous
system, microglia and astrocytes influence inflammation and
neurodegeneration. While microglia regulate pro-inflammatory and
neurotoxic activities in astrocytes, the precise mechanisms remain
unclear. Recent findings suggest that microglia-produced TGFα plays a
role in modulating the pathogenic activities of astrocytes in
experimental models of NDD [23].
To
ascertain the precise involvement of TGF-α in glial activation
following traumatic brain injury, Isuno et al. explored the responses of
astroglial and microglial cells in MMTV-TGF-α positive mice with TGF-α
overexpression induced by a cortical injury. The findings suggested that
TGF-α overexpression has a potential role in influencing neuronal
function [24]. TGFα regulate NF-κB pathogenic activities during CNS
inflammation and it is involved in, neuroprotection, astrogliosis and
prevention of NDD [25].
SIRT6
plays essential roles in the pathophysiology of Alzheimer's disease
(AD), participating in telomere preservation, DNA repair, genome
integrity, energy metabolism, and inflammation factors that collectively
influence lifespan [26]. Recent research indicating the absence of
SIRT6 in AD patients suggests its potential as a novel therapeutic
target in the treatment of AD [26].
Calorie
restriction (CR) involves reducing calorie intake without causing
nutritional deficiencies [8], [9], [10]. Studies in laboratory rodents
have shown that a 30–40 % reduction in ad libitum (AL) food intake can
extend lifespan by 50 % [11]. Two common CR protocols, chronic calorie
restriction (CCR) and intermittent calorie restriction (ICR), are
believed to activate protective mechanisms against neurodegeneration
(ND) and age-related diseases [15], [16]. Despite existing literature
highlighting the protective role of SIRT proteins against age-related
ND, no study has explored the total levels of SIRT 1, 3, and 6 proteins
simultaneously in brain homogenates by ELISA following intermittent
calorie restriction.
In
this study, we hypothesized that "CR modulates SIRT protein levels, and
the type of calorie consumption regulates ND." Applying CCR or ICR
protocols in mice to induce stress[3], [10], [12], [16], [19], [20], we
aimed to determine whether ND would be more pronounced with AL or with
CR.
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