A principal marker of brain vulnerability, stress, aging, and related pathology is represented by lipopigments – lipofuscin and ceroid.
During ontogenesis, neuronal lipopigment accumulations are significantly correlated with important changes in nerve cell morphology and biochemistry.
In the aged neurons, lipopigments are present in all cellular compartments.
Moreover, neuronal lipopigment accumulations coexist with glial lipopigment storage, especially in microglia.
Owing to their transporting properties, and the migration capacity of microglia, glial cells deposit lipopigment clusters in pericapillary areas.
Thus, lipopigment conglomerates appear in the whole nervous tissue, creating specific patterns of lipopigment architectonics.
Direct interrelations, critical lipopigment concentrations,which generate cascades of negative subcellular events, and indirect impairment correlations determine characteristic neuropathologic aging profiles.
These specific and associated negative neuropathologic consequences of lipopigment accumulation have multiple and detrimental impacts on neuron and glia homeostasis, ranging from neuronal function to central nervous system physiology.
Ontogenesis, longevity, and normal and pathological brain aging, correlated with the factors that control, regulate, and disturb central nervous system (CNS) structure and function, open new paths of knowledge and intervention.
Systematic research in comparative zoology, comparative morphology, senescence of mammals, and biogerontology shows interesting connections, such as the following:
- relationships in mammals between the rate of aging (as deduced from maximum life span) and the size of the animal (body weight) and metabolic scales/rates;
- correlations in mammals between longevity and brain size/weight, as an absolute or relative (to body weight) value;
- links between longer-lived species, with a slower rate in the accumulation of lipofuscin and increased resistance of brain to autooxidation, with increasing life span.
Brain senescence in humans is a complicated and heterogeneous process with high regional specificity and individuality.
Therefore, important connections in normal and pathological aging of CNS can be pointed out between:
- neuronal density and different types of glial presence and reactivity;
- brain lipopigments in neurons and glia;
- lipopigments in relationship with mitochondrial pathology (mtDNA mutations and giant mitochondria), anabolic subcellular structures, and lysosomal dysfunction; and lipopigments and Alzheimer pathology (meganeurites, neurofibrillary tangles, and amyloid plaques).
The lipopigments lipofuscin and ceroid display almost identical biophysical, biochemical, and morphological characteristics and properties in their final steps.
By virtue of their implication and negative consequences on neuronal and glial physiology, lipopigments represent a main marker of brain vulnerability, stress, aging, and related pathology.
Lipopigment accumulation in the brain has some important features:
- brain ubiquity: in all the central nervous system regions and zones, from cerebrum to spinal cord;
- presence in all the nervous tissue in whole cellular types, from different kind of neurons to glia and endothelial cells;
- specific patterns of lipopigment architectonics in close relation with senescence and age-related pathology;
- lipopigment accumulation in two stages: stage I – lipopigments increase in number, surface, volume, complexity, in both neurons and glial cells; stage II – lipopigments become constant in inflammatory degenerative nervous disorders (Alzheimer’s and Parkinson’s diseases, etc.).
In aged neurons, lipopigment is present in all cellular compartments, especially in perikaryon areas and dendrites, but also in axons and even in presynaptic components.
Moreover, in neuroglia, from perineuronal glia to neuropil and pericapillary glia, lipopigment storage is present in all cellular partitions: gliosomas, glial arborizations, and capillary end-feet.
As a time-dependent phenomenon, neuronal lipopigment accumulations during ontogenesis, aging, and longevity constantly coexist and are significantly correlated with important negative synergistic metabolic and cell–subcellular events: modifications in neuron/glia index; changes of cyto-, pigmento-, and myelo-architectonics; alterations in the structure and function of subcellular systems.
In aging and aged-related neurodegenerative pathologic conditions, constant expansion of neuronal lipopigments is associated with neuronal loss and simultaneous increase in reactivity and number of neuroglial cells.
Glial activation, the canonical features of mammalian aging, and mediators of inflammatory and degenerative diseases in the brain, basically consist of astrocyte hyperactivity, fibrous phenotype, and microglial activation, increased expression of major histocompatibility complex (MHC) class II antigens, and increased levels of transforming growth factor-beta-1 mRNA (TGFα-1), which are attenuated by caloric restriction.
Neuronal lipopigment conglomerates realize specific brain patterns of lipopigment architectonics and modify neurono- and myelo-architectonics, being correlated with a decrease in the surface/volume of neurosoma, dendritic aberrations, simplification and destruction, axonal enlargement to meganeurites, considerable reduction of cortical myelin, and synaptic loss.
Progressive neuronal lipopigment storage is also associated with increase of oxidative stress, decrease of the antioxidative defense, accumulation of mtDNA mutations, increased number of damaged, defective, impaired, and giant mitochondria with a low rate of degradation, as well as decrease in the number and area of normal and functional healthy mitochondria.
Neuronal lipopigments and anabolic subcellular systems are in an inverse correlation with one another.
The extension of lipopigment clusters is connected with decrease of ribosomal RNA, total RNA, and water-soluble proteins, and consecutive diminution in the number and surface/volume of polyribosomes and rough endoplasmic reticulum.
Neuronal lipopigments and catabolic subcellular systems show interesting correlations.
For example, progressive lipopigment accumulations and aggregations interact and are associated with proteasome instability and inhibition and lysosome dysfunction, deficient and poor function of cellular recycling systems, and finally with accumulations of water-insoluble proteins, oxidized proteins, advanced protein glycation/glycooxidation end-products, advanced lipid peroxidation end-products, as pluri-metabolic sources and compounds of subcellular garbage.
Lipopigment storage interacts negatively with neuron structure and is constantly present and correlated with the appearance and development of cytoskeletal damage, as well as with amyloid deposit and amyloid-related pathologic conditions.
Neuronal lipopigment deposits coexist with large glial lipopigment storage vacuoles in all types of glia.
Thus, the glial paradox appears in brain aging and aged-related pathologic conditions.
Neuroglia – mitotic cells, characterized by a moderate-too high rate of divisions – are overloaded with two types of garbage: lipopigment conglomerates, characteristic of neurons, and phagocytic-degraded neuronal apoptotic bodies.
Microglial cells degrade oxidized extracellular proteins and neuronal apoptotic bodies, subsequent sources of lipopigments.
However, the large amounts of glial lipopigments (often up to 80–90% of the glioplasm) can also be explained by lipopigment neurono-glial transfer.
Glial systems play an important role in collecting neuronal lipopigments.
Owing to their transporting properties and the migratory capacity of microglia, glial cells deposit the lipopigment clusters in pericapillary areas.
These purged mechanisms can be activated and completed by neurometabolic, anti-oxidative, neurovascular, and nootropic therapy.
Direct, causal interrelations and critical lipopigment concentrations, which generate cascades of negative lifelong subcellular events, as well as indirect, associated impairment correlations, determine characteristic neuropathologic aging profiles.
Specific and associated negative neuropathologic consequences of lipopigment storage have multiple and detrimental impacts on neuronal and glial homeostasis, from neuronal function to brain physiology.
Anti-homeostatic actions of oxidative stress (and implicitly lipopigment accumulation and subcellular dysfunction) contribute to the maintenance and magnification of the brain aging cascade in an etiopathogenic direction.
Inversely, in a therapeutic direction, antioxidative medication, drugs for metabolic support/activation of brain homeostasis, and the adapting stimulation in hormesis represent natural ways in anti-aging, rejuvenation, and prolongevity medicine.