Aging refers to the collective physiological, functional, and mental changes that accrue in a biological organism over time. The hallmarks of aging are observable biological patterns of dysfunction that occur with aging. Integral to the aging process is inflammaging, the chronic, low-grade inflammation that occurs with aging.[1] The mechanisms that drive inflammaging and the pathological conditions that arise because of it are bidirectional and involve multiple physiological processes and pathways, many of which directly or indirectly intersect with some of the hallmarks described below. (For more on this, see the "Inflammaging" section later in the article.)

Current research recognizes nine hallmarks of aging.[2]

  • Genomic instability, the increased tendency for DNA mutations (e.g., base deletions, additions, or substitutions) and other genetic changes (e.g., chromosome architecture) to occur over time.

  • Telomere attrition, the shortening of the protective caps on the end of DNA that happens as cells divide over time, leaving DNA more vulnerable to mutations.

  • Epigenetic alterations, non-sequential changes in DNA that accumulate over time and contribute to the loss of proteostasis.

  • Loss of proteostasis, the inability of cells to maintain the levels of proteins and enzymes needed for a cell to function correctly.

  • Deregulated nutrient sensing, the declining responsiveness of cells to changes in fuel availability in the body.

  • Mitochondrial dysfunction, impaired mitochondrial function that occurs over time as mitochondrial membranes and energy production become less efficient.

  • Cellular senescence, the process by which damaged cells terminate normal growth and reproduction cycles in order to prevent injured cells from proliferating.

  • Stem cell exhaustion, a phenomenon that occurs as progenitor cells reproduce to give rise to new specialized cells (e.g., skin, liver, cardiac, skeletal muscle cells) but can be accelerated by environmental exposures.

  • Altered intercellular communication, the diminished capability of cells of different tissues types (e.g., skin, liver, muscle) to communicate their status and behavior to each other.

Mechanisms/biomarkers of aging

The aforementioned hallmarks increase in severity over time for most living organisms, but the rate of declining function is dependent upon a number of genetic and environmental factors specific to each individual. Accelerated biological aging is implicated in most of the chronic diseases common to industrialized nations, such as:[2]

  • Cardiovascular disease
  • Type 2 diabetes
  • Cancer
  • Neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease)

The following section elaborates on the mechanisms and biomarkers associated with the hallmarks of aging.

Genomic instability

Genomic instability refers to an increased tendency for genetic alterations, such as mutations and chromosome rearrangements, to occur over time during cell division. It is a defining characteristic of aging. In humans, genomic instability is often associated with inherited diseases, predisposition to some cancers, and premature aging.

The principal drivers of genomic instability are defects in processes that modulate cell division, such as mutations in genes that participate in DNA repair, uncorrected errors that occur during replication, or broken, missing, rearranged, or extra chromosomes.[3] Cellular checkpoints and DNA damage-response pathways help preserve genomic stability and cell-cycle progression, but these processes decline with aging.[4]

Detecting genomic instability with gamma-H2AX

There are five known histone proteins: H1, H2A, H2B, H3, and H4. Histone 2A has several variants, one of which is H2AX, which plays important roles in DNA repair, specifically non-homologous end joining, a pathway that repairs double-strand breaks. Damage to DNA via exposure to ionizing radiation, certain drugs, or cytotoxic agents induces phosphorylation of a specific amino acid on H2AX.[5]

Phosphorylated H2AX, known as gamma-H2AX, is a robust indicator of DNA damage. As such, it may serve as a prognostic marker for cancer as well as a biomarker for many age-related diseases.[6] [7]

Response to DNA damage

Cellular DNA is subject to tens of thousands of injuries each day that arise from both endogenous sources, such as free radicals produced during normal metabolism, and exogenous sources, such as cytotoxic drugs, ionizing radiation, and cigarette smoke, among others.[8] The DNA damage response pathway is a set of signaling pathways that cells use to maintain genomic integrity and repair damage after injury; however, the efficiency and activity of these pathways are diminished with aging.

The first step in initiating DNA repair is recognition of the damage via injury-specific sensing molecules and subsequent recruitment of signal transducers, primarily enzymes called kinases. Then, various checkpoints and repair systems, including cell cycle regulators, nucleases, helicases, polymerases, and ligases, remove the damage, thus maintaining genomic integrity. Repair systems are injury-specific and include:[9]

  • Non-homologous end-joining and homologous recombination (repair double-strand breaks)
  • Single-strand break repair (repairs damaged DNA strands)
  • Mismatch repair (corrects errors that occur during replication)
  • Base excision repair (reverses oxidative base modifications)
  • Nucleotide excision repair (removes injuries that distort the helix)

Left unrepaired, these injuries can lead to cell death and bodily disease.

Inhibition of histone deacetylases (HDACs) restores genomic stability

HDACs are enzymes that are of particular interest to the field of aging research. They function as "global" transcriptional regulators, influencing gene expression via deacetylation of both histone proteins (molecules that provide structural and functional support to DNA) and non-histone proteins, including a wide range of proteins that regulate gene transcription. HDACs also regulate the activity of critical physiological processes that maintain homeostasis and promote longevity, including cell-cycle regulation, cell growth and differentiation, DNA damage response, and apoptosis (a cellular self-destruct mechanism).[10]

Evidence indicates that dietary compounds that inhibit HDAC activity, such as curcumin, resveratrol, and berberine, show promise as anti-aging therapies, each with varying degrees of evidence.[11] [12] [13] A growing body of evidence indicates that beta-hydroxybutyrate is a robust HDAC inhibitor.[14]

Telomere attrition

Telomeres are distinctive structures composed of short, repetitive sequences of DNA located on the ends of chromosomes. Telomeres form a protective “cap” – a sort of disposable buffer that gradually shortens with age – that prevents chromosomes from losing genes or sticking to other chromosomes during cell division.

Telomere length is commonly measured in leukocytes, a type of white blood cell. The length (in base pairs, see below) serves as a biomarker for a wide range of age-related disorders, including neurodegenerative disease, cardiovascular disease, and cancer, as well as all causes of premature death.[15] [16]

Base pairs are nitrogen-containing molecules (called nucleotides) that form the “rungs” of the ladder-like structure of DNA. The length of most telomeres ranges from 8,000 base pairs in a newborn to 3,000 base pairs in an adult and as low as 1,500 in older adults.[17] The average cell loses 30 to 200 base pairs from the ends of its telomeres each time it divides, contributing to (and serving as a marker of) aging.[18] When the telomeres on a cell’s chromosomes get too short, the chromosome reaches a “critical length,” and the cell stops dividing (senescence) or dies (apoptosis). Shorter telomeres leave DNA more vulnerable to mutations.

Telomerase, a type of reverse transcriptase enzyme, adds specific nucleotide sequences to the ends of existing chromosomes, extending the telomere. Telomerase activity is highly regulated during development, and its activity is almost undetectable in fully developed cells. This lack of activity causes cellular aging. If telomerase is activated in a cell, the cell will continue to grow and divide or become “immortal,” which is important to both aging and cancer. Telomerase enzyme activity has been detected in more than 85 percent of human cancers.[19]

Telomere length is profoundly influenced by the exposome, the totality of non-genetic exposures a person experiences during a lifetime. The exposome comprises both tangible and intangible exposures, ranging from food, air, physical surroundings, microbes, and chemicals to psychological stressors, education level, and financial status, among others, and likely has diverse effects on human health.

Assessing and quantifying the exposome presents challenges, but the length of telomeres may provide a suitable proxy for its assessment. For example, centenarians – people who live to be 100 years old or older – typically have longer telomere lengths than most adults in the 65- to 85-year range.[20] Longer telomeres are associated with several measures of good health. However, scientific evidence suggests that behaviors such as worry, rumination, and anticipatory stress switch on cardiovascular, hormonal, and immunological responses that shorten telomeres.[21]

Epigenetic alterations

Epigenetics is a biological mechanism that regulates gene expression (how and when certain genes are turned on or off). Diet, lifestyle, and environmental exposures can drive epigenetic alterations throughout an individual's lifespan to influence health and disease and can even be passed to subsequent generations. The primary biochemical processes thought to drive epigenetic alterations are DNA methylation and histone modification.

DNA methylation

DNA methylation occurs naturally when a methyl group – a chemical structure containing three hydrogen atoms and one carbon atom – attaches to one of DNA's four nucleotide bases (adenine [A], cytosine [C], guanine [G], or thymine [T]). Methylation creates a biological record of the varied molecular processes that participate in human physiology. The primary regulators of methylation are DNA methyltransferases and ten-eleven translocation(also known as TET) enzymes.[22] Many lifestyle factors promote methylation, including dietary intake, exercise, stress, smoking, and others.[23] As a result, methylation is believed to be reversible.[24]

The most common DNA methylation process involves the addition of a methyl group to one of the carbon atoms in the cytosine base, forming 5-methylcytosine. This addition alters the overall geometry of the DNA strand, influencing gene expression. The majority of 5-methylcytosine is found on areas of the DNA known as CpG islands – short stretches of DNA where the frequency of the cytosine-guanine (CG) sequence is higher than other regions. Methylation of a CpG island in the promoter region of a gene turns off the gene's expression. DNA methylation may promote age-related diseases such as cancer.[24]

Histone modification

Histone modifications, which include acetylation, methylation, phosphorylation, and ubiquitination (as well as others)[25], regulate the activity of chromatin, the coiled structure DNA forms, preventing it from being opened and transcribed (the first step in gene expression and DNA replication) randomly. Chromatin is wrapped around histone proteins that open or close the chromatin, based on whether the histone has been modified. As modifications accumulate over the lifespan, chromatin is harder to open, and gene expression slows. HDAC inhibitors (described above) help release histones, open chromatin, prevent loss of gene expression with aging, and may extend lifespan.[14]

Loss of proteostasis

Proteostasis is a homeostatic mechanism by which the body maintains the proteome, the collective set of proteins produced in the body. The relationship between proteostasis and aging is complex and appears to be bidirectional. That is, aging drives loss of proteostasis, while loss of proteostasis promotes aging. This is seen in age-related neurodegenerative diseases, such as Alzheimer's disease, wherein misfolded proteins aggregate and, in turn, drive disease progression.[26]

Proteostasis involves a wide range of processes, including protein synthesis, folding, modification, transport, and degradation, among others.[27] These varied processes employ a network of cellular components, including chaperones (such as heat shock proteins)[28] and an array of cellular metabolites.[29]

Scientists have not fully characterized all the factors that drive age-related declines in proteostasis, but several candidates have emerged, including accumulation of age-dependent protein damage; impairment of protein synthesis; inability to respond to altered proteostasis demands; and altered cellular metabolites related to age-dependent metabolic changes.[27]

Deregulated nutrient sensing

The body employs a vast array of sensing pathways that detect intra- and extracellular concentrations of fats, amino acids, and sugars. During periods of food abundance, these pathways facilitate growth and storage, whereas during periods of scarcity, they trigger mechanisms that break down and mobilize internal stores. Nutrient sensing pathways are commonly dysregulated in aging but may be enhanced via dietary interventions, such as calorie restriction and intermittent fasting.[30]

Learn more about the beneficial metabolic effects of intermittent fasting in this episode featuring Dr. Mark Mattson.

Important nutrient-sensing pathways that may become dysregulated with age include:

  • Mechanistic target of rapamycin (mTOR), a genetic pathway that senses amino acid concentrations and regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. mTOR integrates other pathways, including insulin, growth factors (such as IGF-1), and amino acids. It plays a key role in mammalian metabolism and physiology, with important roles in the function of tissues, including liver, muscle, white and brown adipose tissue, and the brain.

  • Adenosine monophosphate kinase (AMPK), an enzyme that serves as a master regulator of cellular energy homeostasis. AMPK activation is triggered in response to altered aspects of mitochondrial performance, specifically, elements of the electron transport chain. This, in turn, reduces the AMP/ATP ratio, promoting glycolysis, the breakdown of glucose. AMPK activation declines with aging, reducing autophagy and promoting inflammation.[31]

  • G-protein coupled receptors (GPR), a family of proteins that sense the presence of fatty acids. Interestingly, stimulation of specific GPRs induces pancreatic release of insulin in response to glucose. Blocking the activity of these GPRs contributes to obesity in humans and mice.[32]

Mitochondrial dysfunction

Mitochondria are the key organelle responsible for cellular energy production. Mitochondrial dysfunction is the disruption of normal mitochondrial function that occurs over time as reactive oxygen species damage vulnerable mitochondrial membranes and energy production becomes less efficient.

The principal drivers of mitochondrial dysfunction include loss of inner membrane electrical and chemical potential, altered electron transport chain function, and reduced metabolite transport into the mitochondria.[33] Mitochondrial dysfunction is a driver of many chronic diseases, such as cancer, type 2 diabetes, and cardiovascular disease, and is a prominent feature of aging.[34]

Learn more about cellular senescence in our overview article.

Stem cell exhaustion

Stem cells are undifferentiated cells that have the potential to develop into specialized cells, such as muscle, blood, or brain cells, serving as a repair system for the body. Stem cells can divide and renew themselves over a long time but not indefinitely.

Stem cell exhaustion, the loss of stem cells' capacity to divide, occurs naturally over the lifespan due to a variety of factors, including toxic metabolite accumulation, DNA damage, proteostasis failure, mitochondrial dysfunction, epigenetic remodeling, and environmental exposures.[35] [36] Rejuvenation therapies such as cellular reprogramming may compensate for the effects of stem cell exhaustion.[37]

Altered intercellular communication

Intercellular communication, or signaling, is essential for coordinating the many physiological processes that occur in a multicellular organism. As cells age, they can become senescent, often acquiring a senescence-associated secretory phenotype, or SASP, a characteristic secretory pattern that influences cell signaling.[38] SASP is profoundly pro-inflammatory and immunosuppressive and contributes to the phenomenon of inflammaging.[39]


Inflammaging, a term coined by Dr. Claudio Franceschi, refers to chronic, low-grade inflammation that occurs with aging.[1] This form of inflammation is often referred to as "sterile" because it involves minor immune cell infiltration in the absence of a pathogen.[40] The processes that drive inflammaging and the pathological conditions that arise because of it are bidirectional and involve multiple physiological processes and pathways.

A fundamental component of the inflammaging process is immune system recognition of metabolic, hormonal, and immune stimuli (such as chronic infections or age-related changes in the gut microbiota), thereby promoting an inflammatory environment.[41] In addition, the cellular senescence (see "Cellular senescence" above) that accompanies aging activates pro-inflammatory signaling pathways and drives the release of cytokines, chemokines, and growth factors – evidence of the senescence-associated secretory phenotype (SASP) described above.[42] Other contributors to inflammaging are cellular debris from normal cell death and the accumulation of metabolic byproducts,[43] such as amyloid-beta proteins, which are involved in the pathogenesis of Alzheimer's disease.

Inflammaging likely drives the impaired immune response exhibited among older adults and is both a contributor to and a result of increased infections.[44]

Contributors to interindividual differences in the accumulation of hallmarks of aging


  • Sugar-sweetened soda consumption was associated with shorter telomeres among US adults. Conversely, 100 percent fruit juice consumption was associated with longer telomeres, while diet sodas and noncarbonated sugar-sweetened beverages were not associated with telomere length.[45]
  • A Western dietary pattern high in saturated fat intake and consumption of refined flour, red and processed meat, and sugar-sweetened beverages was associated with shorter telomeres. In contrast, a Mediterranean dietary pattern, rich in plant foods, fish, and seafood, was associated with longer telomeres.[46]
  • Diets high in antioxidants were associated with longer telomeres in children and adolescents.[47]
  • High blood sugar levels increased the rate of cellular senescence in bone marrow stem cells.[48]
  • Virgin olive oil reduced oxidation and DNA breaks compared to sunflower oil.[49]


  • A sedentary lifestyle accelerated aging while exercising reduced cellular senescence.[50]
  • Resistance and endurance exercise increased the production of heat shock proteins, which are large structures that help other proteins maintain their shape, preventing the loss of proteostasis.[51]
  • Regular physical exercise altered DNA methylation patterns, a primary feature of epigenetic change.[51]

Temperature-induced biological stress

Human life is sustainable within a narrow range of temperatures, extending from approximately 27°C (80.6°F) to approximately 42°C (107.6°F). Exposure to temperatures outside this range induces cellular stress and subsequent compensatory responses that may have anti-aging effects.

For example, heat exposure via sauna use induces the activity of heat shock proteins, a large class of proteins that play prominent roles in many cellular processes, including immune function, cell signaling, cell-cycle regulation, and proteome homeostasis.[52] Heat shock proteins directly scavenge reactive oxygen species and support cellular antioxidant capacity through their effects on maintaining glutathione levels.[53] [54] In addition, heat shock proteins promote mitochondrial biogenesis,[55] potentially reversing age-related mitochondrial dysfunction. (See "Mitochondrial dysfunction" above)

Cold exposure via cold-water immersion or cryotherapy induces cold shock proteins, a large family of proteins that respond to cellular stressors such as cold exposure, DNA damage, and hypoxia.[56] Notable cold shock proteins include cold‐inducible RNA binding protein, which promotes cell survival and activates antioxidant enzymes under conditions of mild hypothermia (89.6°F [32°C]), and RNA binding motif 3, or RBM3, which may be neuroprotective.[57] [58] [59] Cold exposure also promotes mitochondrial biogenesis.ref doi='10.20463/jenb.2017.0020'

Supplements and medications

  • Supplementing 1.5 or 2.5 grams of marine omega-3s reduced oxidative stress and increased telomere length; however, telomere lengthening depended on the accumulation of omega-3s in the blood.[60]
  • Metformin, a medication for type 2 diabetes that reduces glucose production in the liver, activates nutrient-sensing pathways that become dysregulated with age.[61]

Other lifestyle factors

  • Sleep loss reduces the length of telomeres and increases cellular senescence.[62]

Topic articles


Relevant publications

  1. ^ a   b Inflamm-aging: An Evolutionary Perspective on Immunosenescence Annals of the New York Academy of Sciences 908, no. 1 (January 2006): 244–54.
  2. ^ a   b The Hallmarks of Aging Cell 153, no. 6 (June 2013): 1194–1217.
  3. ^ Genome instability: a mechanistic view of its causes and consequences Nature Reviews Genetics 9, no. 3 (March 2008): 204–17.
  4. ^ DNA damage checkpoint activation impairs chromatin homeostasis and promotes mitotic catastrophe during aging eLife 8 (November 2019).
  5. ^ Gamma-H2AX - a novel biomarker for DNA double-strand breaks In Vivo 22, no. 3 (2008): 305–9.
  6. ^ gamma-H2AX: Can it be established as a classical cancer prognostic factor? Tumor Biology 39, no. 3 (March 2017): 101042831769593.
  7. ^ Age-Related Disease Association of Endogenous -H2AX Foci in Mononuclear Cells Derived from Leukapheresis PLoS ONE Edited by J. Christopher States. 7, no. 9 (September 2012): e45728.
  8. ^ The DNA Damage Response: Making It Safe to Play with Knives Molecular Cell 40, no. 2 (October 2010): 179–204.
  9. ^ DNA Damage Response and Immune Defense: Links and Mechanisms Frontiers in Genetics 7 (August 2016).
  10. ^ Epigenetic drugs: a novel anti-aging strategy? Frontiers in Genetics 3 (2012).
  11. ^ Epigenetic changes induced by curcumin and other natural compounds Genes &thsemicolon Nutrition 6, no. 2 (April 2011): 93–108.
  12. ^ Histone Deacetylase Inhibition Activity and Molecular Docking of ( E1mu )-Resveratrol: Its Therapeutic Potential in Spinal Muscular Atrophy Chemical Biology &thsemicolon Drug Design 73, no. 3 (March 2009): 355–64.
  13. ^ Plant Isoquinoline Alkaloid Berberine Exhibits Chromatin Remodeling by Modulation of Histone Deacetylase To Induce Growth Arrest and Apoptosis in the A549 Cell Line Journal of Agricultural and Food Chemistry 64, no. 50 (December 2016): 9542–50.
  14. ^ a   b D-beta-hydroxybutyrate extends lifespan in C. elegans Aging 6, no. 8 (August 2014): 621–44.
  15. ^ Leukocyte Telomere Length in Relation to 17 Biomarkers of Cardiovascular Disease Risk: A Cross-Sectional Study of US Adults PLOS Medicine Edited by Kazem Rahimi. 13, no. 11 (November 2016): e1002188.
  16. ^ Leukocyte telomere length and epigenetic-based mortality risk score: associations with all-cause mortality among older adults Epigenetics 13, no. 8 (August 2018): 846–57.
  17. ^ Telomere lengths are characteristic in each human individual Experimental Gerontology 37, no. 4 (April 2002): 523–31.
  18. ^ Telomere length measurement as a clinical biomarker of aging and disease Critical Reviews in Clinical Laboratory Sciences 55, no. 7 (September 2018): 443–65.
  19. ^ Griffith, J. “Telomerase Activity in Human Cancer.” Office of Scientific and Technical Information ({OSTI}), October 2000.
  20. ^ Association of Longer Telomeres With Better Health in Centenarians The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 63, no. 8 (August 2008): 809–12.
  21. ^ Stress appraisals and cellular aging: A key role for anticipatory threat in the relationship between psychological stress and telomere length Brain, Behavior, and Immunity 26, no. 4 (May 2012): 573–79.
  22. ^ TET repression and increased DNMT activity synergistically induce aberrant DNA methylation Journal of Clinical Investigation 130, no. 10 (September 2020): 5370–79.
  23. ^ DNA Methylation of the Human Oxytocin Receptor Gene Promoter Regulates Tissue-Specific Gene Suppression Biochemical and Biophysical Research Communications 289, no. 3 (December 2001): 681–86.
  24. ^ a   b DNA Methylation Clocks in Aging: Categories, Causes, and Consequences Molecular Cell 71, no. 6 (September 2018): 882–95.
  25. ^ Histone modifications and their role in epigenetics of atopy and allergic diseases Allergy, Asthma &thsemicolon Clinical Immunology 14, no. 1 (May 2018).
  26. ^ Widespread Proteome Remodeling and Aggregation in Aging C. elegans Cell 161, no. 4 (May 2015): 919–32.
  27. ^ a   b Recent advances in understanding the role of proteostasis Faculty Reviews 10 (September 2021).
  28. ^ Mitochondrial molecular chaperones: their role in protein translocation Trends in Biochemical Sciences 19, no. 2 (February 1994): 87–92.
  29. ^ Chemical chaperones assist intracellular folding to buffer mutational variations Nature Chemical Biology 8, no. 3 (January 2012): 238–45.
  30. ^ Intermittent metabolic switching, neuroplasticity and brain health Nature Reviews Neuroscience 19, no. 2 (January 2018): 81–94.
  31. ^ AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network Ageing Research Reviews 11, no. 2 (April 2012): 230–41.
  32. ^ Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human Nature 483, no. 7389 (February 2012): 350–54.
  33. ^ Mitochondrial Dysfunction and Chronic Disease: Treatment With Natural Supplements Integr Med (Encinitas) 2014 Aug;13(4):35-43
  34. ^ The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes Frontiers in Molecular Biosciences 8 (May 2021).
  35. ^ Stem cell aging: mechanisms, regulators and therapeutic opportunities Nature Medicine 20, no. 8 (August 2014): 870–80.
  36. ^ Protection of hematopoietic stem cells from stress-induced exhaustion and aging Current Opinion in Hematology 27, no. 4 (May 2020): 225–31.
  37. ^ In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming Cell 167, no. 7 (December 2016): 1719–33.e12.
  38. ^ The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression Annual Review of Pathology: Mechanisms of Disease 5, no. 1 (January 2010): 99–118.
  39. ^ Cellular Senescence and Inflammaging in Age-Related Diseases Mediators of Inflammation 2018 (2018): 1–6.
  40. ^ Inflammaging: a new immune metabolic viewpoint for age-related diseases Nature Reviews Endocrinology 14, no. 10 (July 2018): 576–90.
  41. ^ Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function Aging Cell 11, no. 5 (July 2012): 867–75.
  42. ^ Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor PLoS Biology Edited by Julian Downward. 6, no. 12 (December 2008): e301.
  43. ^ Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes? Frontiers in Immunology 8 (January 2018).
  44. ^ Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention Frontiers in Immunology 10 (September 2019).
  45. ^ Soda and Cell Aging: Associations Between Sugar-Sweetened Beverage Consumption and Leukocyte Telomere Length in Healthy Adults From the National Health and Nutrition Examination Surveys American Journal of Public Health 104, no. 12 (December 2014): 2425–31.
  46. ^ Nutrients, foods, dietary patterns and telomere length: Update of epidemiological studies and randomized trials Metabolism 65, no. 4 (April 2016): 406–15.
  47. ^ Dietary total antioxidant capacity is associated with leukocyte telomere length in a children and adolescent population Clinical Nutrition 34, no. 4 (August 2015): 694–99.
  48. ^ Hyperglycemia Accelerated Endothelial Progenitor Cell Senescence via the Activation of p38 Mitogen-Activated Protein Kinase Circulation Journal 70, no. 8 (2006): 1076–81.
  49. ^ Dietary fat type (virgin olive vs. sunflower oils) affects age-related changes in DNA double-strand-breaks, antioxidant capacity and blood lipids in rats Experimental Gerontology 39, no. 8 (August 2004): 1189–98.
  50. ^ Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue Diabetes 65, no. 6 (March 2016): 1606–15.
  51. ^ a   b Aging Hallmarks: The Benefits of Physical Exercise Frontiers in Endocrinology 9 (May 2018).
  52. ^ Patrick, Rhonda P., and Teresa L. Johnson. “Sauna Use as a Lifestyle Practice to Extend Healthspan” 154 (October 2021): 111509.
  53. ^ Heat stress attenuates skeletal muscle atrophy in hindlimb-unweighted rats Journal of Applied Physiology 88, no. 1 (January 2000): 359–63. doi:10.1152/jappl.2000.88.1.359.
  54. ^ Intermittent hyperthermia enhances skeletal muscle regrowth and attenuates oxidative damage following reloading Journal of Applied Physiology 102, no. 4 (April 2007): 1702–7. doi:10.1152/japplphysiol.00722.2006.
  55. ^ Repeated exposure to heat stress induces mitochondrial adaptation in human skeletal muscle Journal of Applied Physiology 125, no. 5 (November 2018): 1447–55. doi:10.1152/japplphysiol.00383.2018.
  56. ^ Cold shock proteins: from cellular mechanisms to pathophysiology and disease Cell Communication and Signaling 16, no. 1 (September 2018).
  57. ^ Cold-inducible RNA binding protein inhibits H2O2-induced apoptosis in rat cortical neurons Brain Research 1441 (March 2012): 47–52.
  58. ^ Cellular Functions of RNA-Binding Motif Protein 3 (RBM3): Clues in Hypothermia, Cancer Biology and Apoptosis Protein & Peptide Letters 23, no. 9 (August 2016): 828–35.
  59. ^ The RNA-binding protein RBM3 is involved in hypothermia induced neuroprotection Neurobiology of Disease 43, no. 2 (August 2011): 388–96.
  60. ^ Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial Brain Behav Immun 2013 Feb;28:16-24.
  61. ^ Benefits of Metformin in Attenuating the Hallmarks of Aging Cell Metabolism 32, no. 1 (July 2020): 15–30.
  62. ^ Telomere length as a marker of sleep loss and sleep disturbances: a potential link between sleep and cellular senescence Sleep Medicine 16, no. 5 (May 2015): 559–63.

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