Biomarkers of aging are

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

s that could predict functional capacity at some later age better than chronological age. Stated another way, biomarkers of

aging Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...

would give the true "biological age", which may be different from the chronological age. Validated biomarkers of aging would allow for testing interventions to extend lifespan, because changes in the biomarkers would be observable throughout the lifespan of the organism. Although maximum lifespan would be a means of validating biomarkers of aging, it would not be a practical means for long-lived species such as humans because

longitudinal studies A longitudinal study (or longitudinal survey, or panel study) is a research design that involves repeated observations of the same variables (e.g., people) over short or long periods of time (i.e., uses longitudinal data). It is often a type of obs ...

would take far too much time. Ideally, biomarkers of aging should assay the biological process of

and not a predisposition to disease, should cause a minimal amount of trauma to assay in the organism, and should be reproducibly measurable during a short interval compared to the lifespan of the organism. An assemblage of biomarker data for an organism could be termed its "ageotype". Although graying of hair increases with age, hair graying cannot be called a biomarker of ageing. Similarly, skin wrinkles and other common changes seen with aging are not better indicators of future functionality than chronological age. Biogerontologists have continued efforts to find and validate biomarkers of aging, but success thus far has been limited. Levels of CD4 and CD8

memory T cell Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear. Function Antigen-specific memory T cells specific to viruses or other microbial molecules can be found in both ...

s and

naive T cell In immunology, a naive T cell (Th0 cell) is a T cell that has differentiated in the thymus, and successfully undergone the positive and negative processes of central selection in the thymus. Among these are the naive forms of helper T cells ( CD ...

s have been used to give good predictions of the expected lifespan of middle-aged mice. Advances in

big data Though used sometimes loosely partly because of a lack of formal definition, the interpretation that seems to best describe Big data is the one associated with large body of information that we could not comprehend when used only in smaller am ...

analysis allowed for the new types of "aging clocks" to be developed. The

epigenetic clock An epigenetic clock is a biochemical test that can be used to measure age. The test is based on DNA methylation levels, measuring the accumulation of methyl groups to one's DNA molecules. History The strong effects of age on DNA methylation le ...

is a promising biomarker of aging and can accurately predict human chronological age. Basic blood biochemistry and cell counts can also be used to accurately predict the chronological age. Further studies of the hematological clock on the large datasets from South Korean, Canadian, and Eastern European populations demonstrated that biomarkers of aging may be population-specific and predictive of mortality. It is also possible to predict the human chronological age using the transcriptomic clock. The recent introduction of low-power and compact sensors, based on micro-electromechanical systems (

MEMS Microelectromechanical systems (MEMS), also written as micro-electro-mechanical systems (or microelectronic and microelectromechanical systems) and the related micromechatronics and microsystems constitute the technology of microscopic devices, ...

) has led to a new breed of the wearable and affordable devices providing unparalleled opportunities for the collecting and cloud-storing personal digitized activity records. Consequently, modern deep machine learning techniques could be used to produce a proof-of-concept digital biomarker of age in the form of all-causes-mortality predictor from a sufficiently large collection of one week long human physical activity streams augmented by the rich clinical data (including the death register, as provided by, e.g., the

NHANES The National Health and Nutrition Examination Survey (NHANES) is a survey research program conducted by the National Center for Health Statistics (NCHS) to assess the health and nutritional status of adults and children in the United States, and t ...

study).

Epigenetic marks

Loss of histones

A new

epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...

mark found in studies of aging cells is the loss of

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...

s. Most of the evidence shows that loss of histones is linked to cell division. In aging and dividing

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...

MNase-seq (Micrococcal Nuclease sequencing) showed a loss of nucleosomes of ~50%. Proper histone dosage is important in yeast as shown from the extended lifespans seen in strains that are overexpressing histones. A consequence of histone loss in yeast is the amplification of

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

. In younger cells, genes that are most induced with age have specific chromatin structures, such as fuzzy nuclear positioning, lack of a nuclesome depleted region (NDR) at the promoter, weak chromatin phasing, a higher frequency of TATA elements, and higher occupancy of repressive chromatin factors. In older cells, however, the same genes nucleosome loss at the promoter is more prevalent which leads to higher transcription of these genes. This phenomenon is not only seen in yeast, but has also been seen in aging worms, during aging of human diploid primary

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...

, and in

senescent Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence inv ...

human cells. In human primary fibroblasts, reduced synthesis of new histones was seen to be a consequence of shortened

telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...

s that activate the DNA damage response. Loss of core histones may be a general epigenetic mark of aging across many organisms.

Histone variants

In addition to the core histones, H2A, H2B, H3, and H4, there are other versions of the histone proteins that can be significantly different in their sequence and are important for regulating chromatin dynamics. Histone H3.3 is a variant of histone H3 that is incorporated into the genome independent of replication. It is the major form of histone H3 seen in the chromatin of senescent human cells, and it appears that excess H3.3 can drive

senescence Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence inv ...

. There are multiple variants of histone 2, the one most notably implicated in aging is macroH2A. The function of macroH2A has generally been assumed to be transcriptional silencing; most recently, it has been suggested that macroH2A is important in repressing transcription at Senescence-Associated Heterochromatin Foci (SAHF). Chromatin that contains macroH2A is impervious to ATP-dependent remodeling proteins and to the binding of

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

Histone modifications

Increased acetylation of histones contributes to chromatin taking a more

euchromatic Euchromatin (also called "open chromatin") is a lightly packed form of chromatin (DNA, RNA, and protein) that is enriched in genes, and is often (but not always) under active Transcription (genetics), transcription. Euchromatin stands in contrast ...

state as an organism ages, similar to the increased

seen due to the loss of histones. There is also a reduction in the levels of H3K56ac during aging and an increase in the levels of H4K16ac. Increased H4K16ac in old yeast cells is associated with the decline in levels of the

HDAC Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around h ...

Sir2, which can increase the life span when overexpressed. Methylation of histones has been tied to life span regulation in many organisms, specifically H3K4me3, an activating mark, and H4K27me3, a repressing mark. In ''C. elegans'', the loss of any of the three Trithorax proteins that catalyze the trimethylation of H3K4 such as, WDR-5 and the methyltransferases SET-2 and ASH-2, lowers the levels of H3K4me3 and increases lifespan. Loss of the enzyme that demethylates H3K4me3, RB-2, increases H3K4me3 levels in ''C. elegans'' and decreases their life spans. In the

rhesus macaque The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally b ...

brain

prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46, ...

, H3K4me2 increases at promoters and enhancers during postnatal development and

. These increases reflect progressively more active and

ally accessible (or open)

chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...

structures that are often associated with

stress Stress may refer to: Science and medicine * Stress (biology), an organism's response to a stressor such as an environmental condition * Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...

responses such as the

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

response. These changes may form an

memory of stresses and damages experienced by the organism as it develops and ages. UTX-1, a

H3K27me3 H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein. This tri-methylation is associated with the downregulation of nearby genes via t ...

demethylase, plays a critical role in the aging of ''C.elegans'': increased ''utx-1'' expression correlates with a decrease in H3K27me3 and a decrease in lifespan. ''Utx-1'' knockdowns showed an increase in lifespan Changes in H3K27me3 levels also have affects on aging cells in ''Drosophila'' and humans.

DNA methylation

Methylation of DNA is a common modification in

mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

ian cells. The

cytosine Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an am ...

base is methylated and becomes 5-methylcytosine, most often when in the CpG context. Hypermethylation of

CpG islands The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...

is associated with transcriptional repression and hypomethylation of these sites is associated with transcriptional activation. Many studies have shown that there is a loss of DNA methylation during ageing in many species such as, rats, mice, cows, hamsters, and humans. It has also been shown that

DNMT1 DNA (cytosine-5)-methyltransferase 1 is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. In humans, it is encoded by the ''DNMT1'' gene. DNMT1 forms part of the family of ...

and

DNMT3a DNA (cytosine-5)-methyltransferase 3A is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the DNMT3A gene. This enzyme is responsible f ...

decrease with aging and

DNMT3b DNA (cytosine-5)-methyltransferase 3 beta, is an enzyme that in humans in encoded by the DNMT3B gene. Mutation in this gene are associated with immunodeficiency, centromere instability and facial anomalies syndrome. Function CpG methylation i ...

increases. Hypomethylation of DNA can lower genomic stability, induce the reactivation of

transposable element A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transp ...

s, and cause the loss of imprinting, all of which can contribute to

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

progression and

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

Immune biomarkers

Recent data suggests that an increased frequency of senescent CD8+ T cells in the peripheral blood is associated with the development of hyperglycemia from a pre-diabetic state suggestive of senescence playing a role in metabolic aging. Senescent Cd8+ T cells could be utilized as a biomarker to signal the transition from pre-diabetes to overt hyperglycemia. Recently, Hashimoto and coworkers profiled thousands of circulating immune cells from supercentenarians at single-cell resolution. They identified a very unique increase in cytotoxic CD4 T cells in these supercentenarians. Generally, CD4 T-cells have helper, but not cytotoxic, functions under physiological conditions however these supercentenarians, subjected to single cell profiling of their T-cell receptors, revealed accumulations of cytotoxic CD4 T-cells through clonal expansion. The conversion of helper CD4 T-cells to a cytotoxic variety might be an adaptation to the late stage of aging aiding in the fighting infections and potentially enhancing tumor surveillance.

Applications of aging biomarkers

The main mechanisms identified as potential biomarkers of aging are DNA methylation, loss of histones, and histone modification. The uses for biomarkers of aging are ubiquitous and identifying a physical parameter of biological aging would allow humans to determine our true age, mortality, and morbidity. The change in the physical biomarker should be proportional to the change in the age of the species. Thus after establishing a biomarker of aging, humans would be able to dive into research on extending life spans and finding timelines for the arise of potential genetic diseases. One of the applications of this finding would allow for identification of the biological age of a person. DNA methylation uses the structure of dna at different stages of life to determine an age. DNA methylation is the methylation of the cysteine in the CG or Cpg region. The hypermethylation of this region is associated with decreased transcriptional activity and the opposite for hypomethylation. In other words, the more "tightly" held the DNA region then the more stable and "younger" the species. Looking at DNA methylation's properties in tissues, it was found to be almost zero for embryonic tissues, it can be used to determine acceleration of age and the results can be reproduced in chimpanzee tissue.

References

External links

Biomarkers of Aging News Advisory

National Institute on Aging The National Institute on Aging (NIA) is a division of the U.S. National Institutes of Health (NIH), located in Bethesda, Maryland. The NIA itself is headquartered in Baltimore, Maryland. The NIA leads a broad scientific effort to understand the ...

{{Longevity Biogerontology Physiology Senescence Biomarkers