👱🏿 ⛩️ 📴 Diagnosis of aging based on 9 hallmarks of aging signs 👨‍🏫 👃🏻 🏾

“If you cannot measure it, you cannot improve it,” said William Thomson, the great Irish physicist known as Lord Kelvin.

B. Vellas et al., In their new work, proposed their biomarkers of aging for each of the 9 common signs of aging, discussed in the most significant work on aging, “Hallmarks of Aging”.

Here is the principle by which they were guided: “Based on modern literature, for each sign of biological aging, we proposed a biomarker of healthy aging. Our choice was based on their connection with mortality, age-related chronic diseases, senile asthenia and / or impaired function. ”

1. Genomic instability. Micronuclei

As a biomarker of genomic instability, the authors proposed micronuclei determined by micronucleus analysis.

Genetic damage accumulates with age due to external and internal factors. Genome instability results from an imbalance between damage and DNA repair. Damage to chromosomes can be assessed using micronucleus analysis, which measures chromosome degradation. Micronuclei are formed from fragments of chromosomes formed during impaired cell division or apoptosis. The increase in the content of micronucleated cells in the body is associated with aging, cancer, neurodegenerative diseases, and tobacco use.

www.ncbi.nlm.nih.gov/pubmed/21763453?dopt=Abstract
www.ncbi.nlm.nih.gov/pubmed/21164187?dopt=Abstract

Also, studies have shown that micronuclei are associated with senile asthenia (Frailty)

academic. oup.com/biomedgerontology/article/73/7/864/4807480

2. Telomere shortening

Telomeres are the terminal regions of chromosomes that are shortened each time the cells divide. This is one of the best-studied signs of aging, with over 8,000 publications at PubMed to date. The two main methods used to measure telomere length are Southern blot (measuring the size of enzymatically cleaved telomere fragments) and quantitative polymerase chain reaction (qPCR).
In a recent meta-analysis of twenty-five studies (where the number of subjects was n = 121749, 21763 dead), telomere shortening was a predictor of mortality from all causes.

www.ncbi.nlm.nih.gov/pubmed/30254001?dopt=Abstract

3. Epigenetic modifications. DNA methylation clock

Changes in the DNA sequence are not the only age-related genomic changes. Epigenetic modifications, such as DNA methylation, histone modification, chromatin remodeling, affecting gene expression, are also features of aging.

Among them, changes in the methylation of CpG islands are the main regulators of gene expression. Based on these changes, relatively constant between individuals, the Epigenetic DNA Methylation Clock was developed, which, according to the authors, accurately shows the biological age and the risk of developing age-related pathologies.

4. Violation of proteostasis. Clusterin

It is known that intracellular protein homeostasis, or proteostasis, is supported by several quality control mechanisms: protein refolding using chaperone proteins and degradation of the ubiquitin-proteasome system or through autophagy. Due to cell stress, aggregation of abnormal proteins is a sign of aging and age-related diseases such as Alzheimer's.

The clusterin protein (also known as apolipoprotein J) supports normal proteostasis, preventing the accumulation of abnormal proteins. Several studies have shown a relationship between clusterin levels and age-related diseases.

So, Riwanto described that a decrease in HDL-associated clusterin levels is associated with coronary heart disease.

www.ncbi.nlm.nih.gov/pubmed/23349247?dopt=Abstract

In the pathogenesis of Alzheimer's disease, clusterin levels in contrast increase.

www.ncbi.nlm.nih.gov/pubmed/20603455?dopt=Abstract

5. Violation of the regulation of nutrients. Sirtuins

Besides insulin and the IGF-1 signaling pathway, sirtuins are other nutrient sensors with the opposite effect: their signaling pathway is associated with nutrient deficiency and catabolism. Activating sirtuins mimics calorie restriction and improves life expectancy and health.

Sirtuin -1 plays a central role in the survival and regeneration of skeletal muscle cells, as described by Sharples et al.

www.ncbi.nlm.nih.gov/pubmed/25866088?dopt=Abstract

Sirtuin-1 was originally described as a nuclear protein. But recently it was found in serum. In this study, lower levels of serum sirtuin-1 were found in older people, in patients with Alzheimer's disease, compared to younger people.

www.ncbi.nlm.nih.gov/pubmed/23613875?dopt=Abstract

6. Mitochondrial dysfunction. GDF 15 and Apelin

Human aging is usually associated with progressive mitochondrial dysfunction. Among the important parameters involved in this dysfunction, the decrease in the efficiency of the respiratory chain observed during aging is characterized by an increase in the production of reactive oxygen species (ROS), defects in the integrity of mitochondria, and a decrease in the biogenesis of mitochondria (controlled, in particular, by sirtuins).

GDF-15 is a stress-induced cytokine and a member of the superfamily of transforming growth factor β. GDF-15 is considered as a diagnostic marker for hereditary mitochondrial diseases, and potentially as a marker for mitochondrial dysfunction

www.ncbi.nlm.nih.gov/pubmed/27018280?dopt=Abstract

Studies show that exercise-induced apelin, the myokine, can also be considered a putative aging biomarker associated with mitochondrial dysfunction. Apelin enhanced muscle function through mitochondriogenesis, as well as other pathways associated with signs of aging: autophagy, inflammation, and muscle stem cells.

www.nature.com/articles/s41591-018-0131-6

7. Cellular aging. p16Ink4A

Cellular aging is a state of stable cell cycle arrest in combination with phenotypic changes, including the production of pro-inflammatory SASP factors. SASP promotes inflammation and tissue dysfunction. Appearing as a compensatory mechanism aimed at preventing the proliferation of damaged cells, cell aging is induced by various age-related stimuli: telomere shortening, DNA damage and excessive mitogenic signaling, in particular, the tumor suppressor protein p16Ink4a, with epigenetic depression of the ink4 / ark locus.

The expression of p16Ink4A protein increases with aging in various tissues in animals and humans.

www.ncbi.nlm.nih.gov/pubmed/15520862?dopt=Abstract
onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9726.2006.00231.x

It was also shown that transcription of p16Ink4a peripheral blood T-lymphocytes is positively associated with age, tobacco use, physical activity and can be one of the aging biomarkers.

www.ncbi.nlm.nih.gov/pmc/articles/PMC2752333

In addition, in a meta-analysis of 372 GWAS studies aimed at identifying age-related disease polymorphisms, the ink4 / ark locus encoding the p16Ink4a protein was associated with the highest number of diseases, including Alzheimer's disease, cardiovascular disease, cancer and type 2 diabetes.

www.ncbi.nlm.nih.gov/pmc/articles/PMC3444649

8. Stem cell depletion: circulating osteogenic progenitor cells

The reparative and regenerative potential of many tissues decreases with age, which is associated with functional depletion in several stem cell pools (for example, hematopoietic, nerve, mesenchymal and intestinal epithelial stem cells).

Adult stem cells are present in every tissue and organ after development and regenerate damaged tissue throughout life. During aging, stem cell function decreases. Stem cell depletion is seen as an integrative consequence of several of the signs of aging described above, including DNA damage, epigenetic changes, telomere shortening, cell aging, and mitochondrial dysfunction.

But stem cell depletion is difficult to measure non-invasively until its clinical consequences, such as anemia and cytopenia (i.e., cell deficiency) for hematopoietic stem cells, as well as sarcopenia for muscle stem cells and decreased bowel function for intestinal epithelial stem cells, occur. Until now, there is insufficient data on potential biomarkers of this sign of aging. Circulating osteogenic progenitor cells have been proposed as a surrogate marker for a population of mesenchymal stem cells in the bone marrow.

asbmr.onlinelibrary.wiley.com/doi/full/10.1002/jbmr.370

The percentage of osteogenic progenitor cells is inversely correlated with age. Also, lower levels of these cells were associated with asthenia, lower physical performance (measured by grip strength and walking speed) and disability, regardless of age and associated pathology.

academic.oup.com/biomedgerontology/article/71/9/1124/2605419

9. Altered Cell-to-Cell Communication: Inflammasomes and IMM-AGE

Aging is associated with changes in the connections between cells and chronic inflammation, inflammaging. This inflammation is seen as a consequence of several of the signs of aging described above, including cell aging (via SASP) and loss of proteostasis, since improperly folded proteins are a danger signal that triggers an innate immune response.

One of the main pathways of inflammation is the signal path of inflammas. Inflammasoma is a complex system of intracellular proteins that collect when stress / danger signals are detected and trigger the maturation and release of pro-inflammatory cytokines (interleukin-1β and interleukin-18). Mouse models lacking the NLRP3 inflammasome demonstrate a decrease in inflammation, glucose intolerance, hippocampal degeneration, and neuroinflammation.

www.ncbi.nlm.nih.gov/pmc/articles/PMC4017327

In the elderly, from 60 to 90 years, activation of inflammasomes (measured by expression of nlcrc4 and nlrc5 genes in whole blood cells and production of interleukin-1β) was positively associated with arterial hypertension and arterial stiffness and negatively associated with personal and family longevity.

www.ncbi.nlm.nih.gov/pubmed/28092664?dopt=Abstract Cholesterol

crystals and β-amyloid proteins can initiate the assembly of inflammatory complexes with inflammasomes, this pathway is involved in the progression of atherosclerotic lesions and neuroinflammation in Alzheimer's disease.

www.ncbi.nlm.nih.gov/pmc/articles/PMC2946640
www.ncbi.nlm.nih.gov/pmc/articles/PMC3812809

In addition to inflammation, immunosenescence includes quantitative and functional changes in many factors of both the innate and adaptive parts of the immune system.

Immunosenescence can aggravate the aging process associated with the signs of aging described above, in particular due to the inability to destroy pathogens, as well as precancerous cells, aging cells and malformed proteins. A. Alpert et al. Have created an IMM-AGE trajectory of immune aging, based on which it is possible to predict mortality risks from all causes.

www.ncbi.nlm.nih.gov/pmc/articles/PMC6686855

Article: “Revision of the signs of aging to identify markers of biological age”

Diagnosis of aging based on 9 hallmarks of aging signs