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including genomic instability and mutations, epigenetic modifi- cation, loss of proteostasis, mitochondrial dysfunction and oxida- tive stress, dysregulated nutrient sensing, increased cell senes- cence, decreased stemness, and altered intercellular commu- nication (Figure 1).[5] In each individual, these processes likely have a different probability of occurrence and contribution to ag- ing depending on pre-programmed (epi)genomic factors and/or the randomly fluctuating environment.[10] Biomarkers that can track the initial steps of aging progression at the molecular and cellular level seem promising, particularly in terms of a rising trend to counteract aging at early-stages by direct molecular and cellular interventions, before the degenerative processes become profoundly deleterious and/or spread throughout the body.

KseniaS.Kudryashova,Ph.D., wheresheconductsanalytical Sheisalsoaresearchscientist attheShemyakin-Ovchinnikov InstituteofBioorganicChem- istryoftheRussianAcademy ofSciencesandaprincipal engineerintheDepartment ofBioengineeringoftheBio- logicalFacultyatLomonosov MoscowStateUniversity.  

2.1. Genomic Instability and Mutations

2.2. Loss of Proteostasis

One of the most potent intracellular processes known to contribute to aging is DNA damage driven by endogenous (metabolic stress, “end-replication problem”) or environmental (radiation, genotoxic chemicals) factors. The defects in the DNA repair system that emerge and accumulate with time lead to genomic instability, characterized by a high frequency of muta- tions, chromosome aberration, and/or aneuploidy. This genomic instability is known to be a prerequisite for the development of cancer and may contribute to particular degenerative diseases, such as Alzheimer’s.[11] Double strand breaks, which are the most critical lesions in terms of cell fate, can be obtained by 𝛾 immunolocalization of DNA damage-induced histone -H2AX (phosphorylated form of the histone variant H2AX) or by other specialized proteins involved in DNA repair machinery.[12] More detailed measures of DNA damage can be performed by DNA sequencing; however, this is not as easy as it sounds since each cell in a tissue acquires different mutations that get lost in bulk sequencing efforts. Therefore, single cell DNA sequencing is required, and recent studies have been performed to assess mutation rate with age.[13]

Cellular protein homeostasis (proteostasis) is maintained by the proteostasis network machinery that orchestrates protein synthe- sis, folding, and degradation. Proteostasis efficiency decreases with time, especially in non- or minimally-dividing cells, such as skeletal muscle and neurons, which are forced to deal with accumulating protein waste, and contributes to many aging- associated diseases.[20,21] For example, protein aggregation is a common feature of neurodegenerative diseases like Alzheimer’s and Parkinson’s.[22] On the cellular level, loss or dysfunction of proteostasis causes the accumulation of unfolded or mis- folded proteins and protein aggregates in the cytoplasm and in organelles.[21] Impaired proteostasis can be detected directly by 𝛽 the formation of aggregates, either ordered (amyloid and hyper- 𝛼 phosphorylated tau in Alzheimer’s disease) or amorphous ( - 𝛼 crystallin in cataracts; -synuclein of Lewy bodies in Parkinson’s disease), or indirectly by increased production of proteostasis network machinery (lysosomal 𝛽 -galactosidase in senescence[23]; chaperone Hsp70 as a marker of oxidative stress[24]). Moreover, the integrity of the proteome can be efficiently examined in pro- teomics studies (see below).

An important type of DNA damage is the shortening of telom- eric repeat sequences at the end of chromosomes during DNA replication in most somatic cells,[14] or as a result of cumula- tive oxidative stress.[15] The critical shortening of telomere length (TL) may lead to permanent cell cycle arrest, also known as replicative senescence. TL tends to decline gradually over the hu- man lifespan and this decline is accelerated in many age-related diseases.[8] Centenarians and their offspring have been found to have longer telomeres relative to controls.[16] However, the use of TL as a biomarker of overall aging is still a debated issue, because TL inconsistently predicts clinical and functional out- comes, life expectancy, and death.[17,18] Besides advanced age, telomere attrition is known to occur in mid-life as a result of stress, infections, or diseases,[19] raising the question of whether telomere attrition is a cause, a consequence, or merely coinci- dent with the aging process. In humans, TL is typically measured in leukocytes or peripheral blood mononuclear cells (PBMC), but it is questionable whether this reflects the whole-body aging process, rather than tissue-specific changes (e.g., hematopoietic stem cell population).[17] These measurements may also be sub- ject to bias, because each established method measures slightly different parameters.[17]

2.3. Mitochondrial Dysfunction and Oxidative Stress