Fundamental Clock of Biological Aging: Convergence of Molecular, Neurodegenerative, Cognitive, and Psychiatric Pathways

    

    

    Figure 2a: Neuroanatomy of stress.
Schematic representation of primarily neuroanatomical substrates responsible for physical (pink) and psychological (blue) stressors processing. Upper panels show
that neural processing for different types of stressors detection and appraisal of the situation engage several structures, which may overlap at some instances on
human and rodent brain (A,B, respectively). Bottom panels represent how physical and psychogenic stressors require engagement of different networks (C, D,
respectively). Adapted from [Godoy et al. 2018].
    

Several types of biologic macromolecules, including DNA, proteins, and lipids, exhibit two interactive (co-existing) characters. First- prevalent chirality [10] and, second, vulnerability to multiple types of aberrant modifications [11]. Prevalent molecular chirality results from natural selection (NS), providing the functionality of DNA, proteins, and lipids along with perceptual and cognitive abilities to live organisms. However, several biomolecular structures, including amyloids, are known as the by-products of the main evolutionary pathway. Aberrant malfunctional structures containing D-amino acids (D-AAs) are the main contributors to the disregulation of neuronal signaling, biological aging, and various disease conditions [12].

Aging, as manifested in the neurodegenerative and psychiatric disorders, is associated with the progressive decline of functions at the molecular, cellular, organ, and organism levels [13-16].

At the molecular level, aging is associated with the impact of physical, environmental, and psychological stressors [7-24]. Acute and chronic psychological stressors are characterized as complicated constructs capable to induce the changes at ANA and protein levels [25,26]. In particular, the neuropathology of schizophrenia is characterized by the convergence of morphological, cellular, and molecular correlates [27-30]. The most common pathways of schizophrenia and neurodegeneration include abnormalities in glutamatergic neurotransmission, altered synaptic plasticity, and elevated brain level of Amyloid-beta (A-b) [31,32]. During the last decade, the reciprocal influences of biology, psychology, behavioral, and social factors on health and illness gain significant attention. But the effect of psychological stressors on spontaneous biological events only in the embryonic state [29,30,33]. It is known that people exposed to major psychological stressors in early life, exhibit an elevated rates mortality from chronic diseases of aging [34]. The impact of psychological stressors on spontaneous, age-associated Post-Translational Modifications (PTMs) of protein remains unexplained. In our view, the critical mechanism underlying the link between PSs and lifespan is spontaneous PTMs.

Organism Level

At the organism level, the age-related decline in cognitive function includes compromised memory, language, critical thinking, and decision-making. Impaired cognition affects the psychologicalbehavioral functions, including social communicants and selfperception, leading to psychological stress associated with a range of psychopathologies. Psychological stress, in turn, is a significant determinant of cognitive decline. Age-associated deterioration of cognition and psychological functions correlates with neuronal degeneration, misfolding, disfunction, and aggregation of synapseassociated proteins and peptides, including NMDA receptors, A-β, TAU, neuroligins, neurexins, and many others [33]. An emerging concept proposes that molecular and sub-cellular structures “sense, integrate, and transduce psychosocial and behavioral factors”, suggesting the reciprocal causation between molecular, cognitive and psychological factors [34-41].

The psychological perspective of aging, seeing through molecular and cell biology prism, helps to understand the complex interrelationships among protein folding, cell signaling, brain structure, cognition, and behavior for both healthy and pathological trajectories [42,43].

Universal Biological Clocks of Aging

The perceptual and cognitive representations of the external world are associated with internal events at the different levels of biological organization.

At the cellular level, cognitive representations are reflected in neuronal representations [44] that are linked to many biomolecular events.

At the molecular level, the fundamental age-related biological clocks are associated with the alterations in the DNA [44-46] lipids [47], proteins [14,15], and interaction between them [46,48]. All molecular clocks contain chronological and biological information related to genetic and epigenetic impacts [49].

At the protein level, the age-related changes are documented in protein transcription, translation, and PTMs. At the same time, neuronal representations are linked to the dynamic system of enzymatic PTMs. It is well-documented that the dysregulation of PTMs leads to a range of neurological alterations (including intellectual disability, learning and memory impairments, autistic-like features, and seizures) [15,16,50] and aging [51]. Aberrant PTMs can potentially be used as the biological indicators of acute psychological and cognitive states. At PTMs domains, the significant age induced changes are observed in the enzymatic PTMs. Most dramatic agerelated changes occur in the level of protein phosphorylation (Figure 2b) [14].

    

    

    Figure 2b: Common and organ-specific alterations of the proteome in old rats.
(A and B) We identified only 48 transcripts affected at the level of translation output (A) and eight proteins affected at the level of protein abundance (B) that were
altered in both brain and liver. The most represented gene ontology (GO) terms among consistently affected transcripts are shown in (A) while the five consistently
affected proteins are indicated in (B). (C-F) Functional enrichment was performed on the list of quantified transcripts and proteins that were ranked according to
the level of differential expression (fold change) using (Eden et al., 2009). Displayed GO terms are representative cases selected from among those significantly
enriched (cut-off for transcripts: q value < 0.05, minimum number of transcript > 4, fold enrichment ≥2; for proteins the same criteria were applied with the exception
of q value < 0.2). The fold enrichments are plotted using positive values for terms enriched in transcripts/proteins that are increased in old animals or using negative
values for terms enriched in transcripts/proteins that are decreased in old animals. Adopted from [14].