BioVector
Longevity ScienceRead time: 12 min

The 14 Hallmarks
of Aging

The biological clock does not tick at the same rate for everyone. In modern longevity research, aging is not seen as an inevitable fate, but as a cumulative process of defined cellular dysfunctions – the "Hallmarks".

The Longevity Dividend

Targeted interventions in the Hallmarks of Aging slow the rate of cellular decay. The gap between the two curves is your actual gained healthspan.

CELLULAR DECAYAGE (YEARS)GAINED HEALTHSPAN
Standard Trajectory
Optimized Biological Age

Genomic Instability

Genomic instability represents the accumulation of genetic damage over time, manifesting as mutations, chromosomal rearrangements, and copy number variations, which compromise cellular integrity and function. This persistent assault on the genome is a foundational driver of aging, directly impacting cellular viability and tissue homeostasis 1.

The integrity of the genome is under constant threat from both endogenous processes, such as replication errors and reactive oxygen species (ROS), and exogenous factors, including radiation and chemical mutagens. While robust repair mechanisms exist, their efficiency declines with age, leading to a net accumulation of damage 2.

Mechanisms of Genomic Instability

  • DNA Damage Accumulation: Increased incidence of double-strand breaks, single-strand breaks, and base modifications due to oxidative stress, replication errors, and environmental insults.
  • Impaired DNA Repair Pathways: Age-related decline in the efficacy of DNA repair systems, including nucleotide excision repair (NER), base excision repair (BER), and homologous recombination (HR), leading to unrepaired lesions.
  • Chromosomal Aberrations: Increased frequency of aneuploidy, translocations, and deletions, disrupting gene dosage and cellular programming.
  • Transposable Element Reactivation: Deregulation of epigenetic silencing mechanisms can lead to the re-activation and transposition of retrotransposons, causing insertional mutagenesis 3.

Telomere Attrition

Telomere attrition refers to the progressive shortening of telomeres, the protective caps at the ends of chromosomes, with each cell division, ultimately triggering cellular senescence or apoptosis. This intrinsic molecular clock limits the replicative capacity of somatic cells, acting as a critical determinant of cellular lifespan 4.

Telomeres consist of repetitive DNA sequences and associated proteins that shield chromosome ends from degradation and fusion. Due to the "end-replication problem" and oxidative damage, telomeres progressively shorten. Once a critical length is reached, DNA damage response pathways are activated, signaling replicative exhaustion 5.

Mechanisms of Telomere Attrition

  • End-Replication Problem: DNA polymerase cannot fully replicate the very ends of linear chromosomes, leading to a loss of telomeric DNA with each cell division.
  • Oxidative Stress: Reactive oxygen species induce guanine oxidation within telomeric repeats, leading to single-strand breaks and accelerated shortening.
  • Inflammation: Chronic inflammation can increase cellular turnover and oxidative stress, further contributing to telomere erosion.
  • Telomerase Insufficiency: Most somatic cells express very low or no telomerase, the enzyme responsible for telomere elongation, preventing the replenishment of lost telomeric sequences 6.

Epigenetic Alterations

Epigenetic alterations encompass age-related changes in DNA methylation patterns, histone modifications, and non-coding RNA expression, which collectively modify gene expression without altering the underlying DNA sequence. These changes disrupt cellular identity and function, contributing to the dysregulation characteristic of aging 7.

The epigenome acts as an interface between the genome and the environment, orchestrating gene expression programs essential for development and cellular differentiation. With age, the epigenome undergoes widespread destabilization, leading to both global hypomethylation and localized hypermethylation, alongside altered histone marks, impacting chromatin accessibility and transcriptional fidelity 8.

Mechanisms of Epigenetic Alterations

  • DNA Methylation Changes: Global loss of methylation (hypomethylation) and specific gains of methylation (hypermethylation) at CpG islands, particularly in promoter regions, leading to aberrant gene silencing or activation.
  • Histone Modification Dysregulation: Alterations in acetylation, methylation, phosphorylation, and ubiquitination patterns of histones, impacting chromatin structure and gene accessibility.
  • Chromatin Remodeling Impairment: Decreased efficiency of ATP-dependent chromatin remodelers, leading to less dynamic and more rigid chromatin states.
  • Non-coding RNA Dysregulation: Changes in the expression and function of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) that regulate gene expression post-transcriptionally 9.

Loss of Proteostasis

Loss of proteostasis refers to the age-dependent decline in the cellular machinery responsible for maintaining protein quality control, leading to the accumulation of misfolded, aggregated, and damaged proteins. This disruption impairs cellular function, contributes to proteotoxic stress, and is implicated in numerous age-related pathologies 10.

The proteostasis network, comprising chaperones, proteasomes, and lysosomes, ensures that proteins are correctly folded, trafficked, and degraded. With advancing age, the capacity of this network diminishes, resulting in an imbalance between protein synthesis, folding, and degradation, leading to the accumulation of dysfunctional proteins 11.

Mechanisms of Proteostasis Impairment

  • Chaperone System Dysfunction: Reduced expression or activity of heat shock proteins (HSPs) and other molecular chaperones, impairing protein folding and refolding.
  • Ubiquitin-Proteasome System (UPS) Decline: Decreased efficiency of the UPS, responsible for degrading short-lived and misfolded proteins, leading to their accumulation.
  • Lysosomal Dysfunction: Impaired lysosomal activity, affecting the degradation of long-lived proteins, organelles, and aggregated material.
  • Increased Protein Damage: Elevated levels of oxidative damage, glycation, and deamidation of proteins, rendering them more prone to misfolding and aggregation 12.

Deregulated Nutrient Sensing

Deregulated nutrient sensing describes the age-related impairment of cellular pathways that monitor nutrient availability and modulate metabolic responses, leading to chronic activation of anabolic pathways and reduced stress resistance. This dysregulation contributes to metabolic dysfunction and accelerates aging 13.

Key nutrient-sensing pathways, including the insulin/IGF-1 signaling (IIS) pathway, mTOR (mechanistic target of rapamycin), and AMPK (AMP-activated protein kinase), play crucial roles in regulating metabolism, growth, and stress responses. In aging, these pathways often become dysregulated, favoring growth and storage over repair and maintenance 14.

Mechanisms of Deregulated Nutrient Sensing

  • Insulin/IGF-1 Signaling (IIS) Hyperactivity: Chronic activation of the IIS pathway, often due to insulin resistance, promotes anabolic processes and suppresses stress resistance and longevity pathways.
  • mTOR Pathway Overactivation: Persistent activation of mTOR, particularly mTORC1, promotes protein synthesis and cell growth while inhibiting catabolic processes like autophagy.
  • AMPK Pathway Hypoactivity: Reduced activity of AMPK, a key sensor of low energy states, diminishes its ability to activate catabolic processes and promote cellular repair.
  • Sirtuin Dysfunction: Altered activity of sirtuins, NAD+-dependent deacetylases that link metabolism to epigenetic regulation, impairing their role in stress response and longevity 15.

Mitochondrial Dysfunction

Mitochondrial dysfunction refers to the age-associated decline in mitochondrial efficiency, characterized by reduced ATP production, increased reactive oxygen species (ROS) generation, and impaired mitochondrial dynamics and quality control. This compromises cellular energy supply and exacerbates oxidative stress, contributing significantly to the aging phenotype 16.

Mitochondria are central to cellular energy metabolism, producing the vast majority of ATP through oxidative phosphorylation. They are also critical for calcium homeostasis, apoptosis, and redox signaling. With age, mitochondria accumulate damage, exhibit morphological abnormalities, and become less efficient, creating a vicious cycle of energy deficit and oxidative damage 17.

Mechanisms of Mitochondrial Dysfunction

  • Reduced ATP Production: Decline in the activity of electron transport chain (ETC) complexes, leading to decreased oxidative phosphorylation efficiency.
  • Increased ROS Production: Enhanced leakage of electrons from the ETC, resulting in elevated generation of superoxide and other reactive oxygen species, causing oxidative damage to macromolecules.
  • Accumulation of Mitochondrial DNA (mtDNA) Mutations: mtDNA is particularly susceptible to oxidative damage and has less robust repair mechanisms than nuclear DNA, leading to an accumulation of mutations that impair mitochondrial function.
  • Impaired Mitochondrial Dynamics and Biogenesis: Dysregulation of mitochondrial fusion and fission processes, leading to fragmented or overly fused mitochondria, and reduced biogenesis, limiting the production of new, healthy mitochondria 18.

Cellular Senescence

Cellular senescence is a state of irreversible cell cycle arrest in response to various stressors, characterized by distinct phenotypic changes, including altered gene expression and the secretion of pro-inflammatory factors. Senescent cells accumulate in tissues with age, contributing to chronic inflammation and tissue dysfunction 19.

Senescence serves as a tumor-suppressive mechanism in young organisms, preventing the proliferation of damaged cells. However, the persistent presence of senescent cells in aged tissues, due to inefficient clearance, becomes detrimental. They secrete the Senescence-Associated Secretory Phenotype (SASP), a complex mixture of cytokines, chemokines, growth factors, and proteases 20.

Mechanisms of Cellular Senescence

  • Telomere Shortening: Critically short telomeres activate DNA damage response pathways, leading to cell cycle arrest.
  • Oncogene Activation: Activation of specific oncogenes can induce premature senescence (oncogene-induced senescence) as a protective mechanism.
  • Oxidative Stress and DNA Damage: Accumulation of DNA damage from ROS or other genotoxic agents can trigger senescence.
  • Mitochondrial Dysfunction: Impaired mitochondrial function can contribute to the establishment and maintenance of the senescent phenotype, including SASP production.
  • SASP Secretion: Senescent cells release a diverse array of molecules that promote inflammation, extracellular matrix remodeling, and can induce senescence in neighboring cells 21.

Stem Cell Exhaustion

Stem cell exhaustion refers to the age-related decline in the number, proliferative capacity, and differentiation potential of tissue-specific stem cells, impairing the regenerative capacity of tissues and organs. This hallmark underlies the reduced ability of aged organisms to repair damage and maintain tissue homeostasis 22.

Adult stem cells are crucial for tissue maintenance and repair throughout life. They possess the unique abilities of self-renewal and differentiation into specialized cell types. With age, stem cell pools become depleted, their functional properties diminish, and their microenvironment (niche) becomes less supportive, leading to impaired tissue regeneration 23.

Mechanisms of Stem Cell Exhaustion

  • Accumulation of DNA Damage: Stem cells are not immune to genomic instability, and accumulated DNA damage can impair their function or trigger senescence/apoptosis.
  • Epigenetic Drift: Age-related epigenetic changes can alter gene expression profiles in stem cells, affecting their self-renewal and differentiation potential.
  • Mitochondrial Dysfunction: Impaired mitochondrial function in stem cells can reduce their energy supply and increase oxidative stress, compromising their viability and function.
  • Altered Stem Cell Niche: The microenvironment supporting stem cells undergoes age-related changes, including altered growth factor signaling, increased inflammation, and changes in extracellular matrix composition, making it less conducive to stem cell function.
  • Reduced Autophagy: Impaired autophagy in stem cells can lead to the accumulation of damaged organelles and proteins, compromising their health and function 24.

Altered Intercellular Communication

Altered intercellular communication encompasses age-related changes in signaling pathways, neurohormonal regulation, and immune cell function, leading to systemic dysregulation and chronic inflammation. This hallmark highlights the breakdown of coordinated cellular and tissue responses essential for maintaining organismal health 25.

Effective communication between cells and tissues is vital for maintaining physiological balance. With age, this intricate network becomes compromised. This includes changes in paracrine and endocrine signaling, neurotransmission, and the immune system's ability to distinguish self from non-self, contributing to a pro-inflammatory state 26.

Mechanisms of Altered Intercellular Communication

  • Neurohormonal Dysregulation: Age-related decline in the function of the hypothalamus-pituitary-adrenal (HPA) axis, sympathetic nervous system, and other endocrine glands, leading to hormonal imbalances.
  • Immunosenescence: Age-related decline in immune function, characterized by reduced naive T-cell output, impaired B-cell responses, and chronic low-grade inflammation (inflammaging).
  • SASP Secretion from Senescent Cells: The pro-inflammatory and tissue-remodeling factors secreted by senescent cells directly impact neighboring cells and contribute to systemic inflammation.
  • Gap Junction Dysfunction: Altered expression and function of gap junction proteins, impairing direct cell-to-cell communication.
  • Extracellular Vesicle Changes: Alterations in the composition and function of exosomes and other extracellular vesicles, which mediate intercellular communication 27.

Chronic Inflammation (Inflammaging)

Chronic inflammation, or "inflammaging," describes the persistent, low-grade, sterile systemic inflammation that characterizes aging, driven by various endogenous stressors and contributing to numerous age-related diseases. This hallmark is a critical component of altered intercellular communication but warrants distinct emphasis due to its pervasive impact 28.

Inflammaging is not typically caused by infection but rather by the accumulation of cellular debris, damaged macromolecules, senescent cells, and dysbiotic microbiota. This chronic activation of innate immune pathways, without resolution, creates a pro-inflammatory environment that damages tissues and accelerates aging processes 29.

Mechanisms of Chronic Inflammation

  • Accumulation of DAMPs (Damage-Associated Molecular Patterns): Release of intracellular molecules (e.g., mtDNA, ATP, HMGB1) from damaged or dying cells, activating innate immune receptors like TLRs and inflammasomes.
  • Senescent Cell Accumulation: Senescent cells secrete the SASP, a potent mix of pro-inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) and chemokines.
  • Microbiota Dysbiosis: Alterations in gut microbiota composition can lead to increased gut permeability and translocation of microbial products (e.g., LPS) into the systemic circulation, triggering inflammation.
  • Mitochondrial Dysfunction: Dysfunctional mitochondria release mtDNA and other components that act as DAMPs, activating inflammatory pathways.
  • Adipose Tissue Dysfunction: Aged adipose tissue becomes inflamed, releasing pro-inflammatory adipokines and contributing to systemic inflammation 30.

Microbiome Dysbiosis

Microbiome dysbiosis refers to the age-related alterations in the composition, diversity, and functional output of the commensal microbial communities, particularly in the gut, leading to impaired host-microbe interactions and systemic inflammation. This disruption impacts nutrient metabolism, immune function, and overall health 31.

The human microbiome, especially the gut microbiota, plays a crucial role in host physiology, including digestion, vitamin synthesis, immune system development, and protection against pathogens. With age, the gut microbiome typically exhibits reduced diversity, an increase in pro-inflammatory species, and a decrease in beneficial bacteria, contributing to inflammaging and metabolic dysfunction 32.

Mechanisms of Microbiome Dysbiosis

  • Reduced Microbial Diversity: A decrease in the richness and evenness of microbial species, often associated with a less resilient and less functionally diverse ecosystem.
  • Shift in Microbial Composition: An increase in potentially pathogenic or pro-inflammatory bacteria (e.g., Proteobacteria) and a decrease in beneficial, short-chain fatty acid (SCFA)-producing bacteria (e.g., Bifidobacterium, Faecalibacterium prausnitzii).
  • Increased Gut Permeability ("Leaky Gut"): Dysbiosis can compromise the integrity of the intestinal barrier, allowing microbial products (e.g., lipopolysaccharides, LPS) to translocate into the systemic circulation, triggering inflammation.
  • Altered Metabolite Production: Changes in microbial composition lead to altered production of key metabolites, such as SCFAs, which are crucial for gut health and systemic immune modulation.
  • Dietary and Lifestyle Factors: Age-related changes in diet, medication use, and physical activity can significantly influence microbiome composition and function 33.

Macroautophagy Impairment

Macroautophagy impairment denotes the age-related decline in the efficiency of macroautophagy, a fundamental cellular process for degrading and recycling damaged organelles and proteins, leading to the accumulation of cellular waste and compromised cellular health. This contributes to proteostasis loss and mitochondrial dysfunction 34.

Autophagy (self-eating) is a catabolic process essential for cellular quality control, nutrient recycling, and adaptation to stress. It involves the formation of autophagosomes that engulf cytoplasmic components, which are then delivered to lysosomes for degradation. With age, the entire autophagic flux, from initiation to lysosomal fusion and degradation, becomes less efficient 35.

Mechanisms of Macroautophagy Impairment

  • Reduced Autophagosome Formation: Decreased expression or activity of key autophagy-related genes (ATGs) and upstream regulators, leading to fewer autophagosomes.
  • Impaired Autophagosome Maturation: Defective fusion of autophagosomes with lysosomes, preventing the delivery of cargo for degradation.
  • Lysosomal Dysfunction: Age-related decline in lysosomal acidity and enzymatic activity, compromising the final degradation step of autophagy.
  • Deregulated Nutrient Sensing Pathways: Overactivation of mTOR and reduced activity of AMPK can directly inhibit autophagy.
  • Accumulation of Autophagic Substrates: Impaired autophagy leads to the buildup of damaged mitochondria (mitophagy), aggregated proteins, and other cellular debris, further stressing the cell 36.

Altered Mechanical Properties

Altered mechanical properties refer to the age-related changes in the physical characteristics of cells, tissues, and the extracellular matrix (ECM), impacting cellular function, tissue integrity, and organ performance. This hallmark highlights the importance of biomechanical cues in maintaining cellular and tissue homeostasis 37.

The mechanical environment plays a critical role in regulating cell behavior, including proliferation, differentiation, and migration. With age, tissues become stiffer, less elastic, and their cellular components exhibit altered mechanosensing and mechanotransduction, contributing to organ dysfunction and disease 38.

Mechanisms of Altered Mechanical Properties

  • Extracellular Matrix (ECM) Stiffening: Increased cross-linking of ECM proteins (e.g., collagen, elastin) due to advanced glycation end-products (AGEs) and altered enzymatic activity, leading to reduced elasticity and increased stiffness.
  • Cellular Stiffness: Age-related changes in cytoskeletal components (actin, microtubules) and nuclear lamina proteins (lamins) can increase cellular and nuclear stiffness, affecting gene expression and mechanosensing.
  • Impaired Mechanotransduction: Dysregulation of cellular pathways that sense and respond to mechanical cues (e.g., integrin signaling, YAP/TAZ pathway), leading to aberrant cellular responses.
  • Loss of Tissue Homeostasis: Changes in mechanical properties can disrupt cell-cell and cell-ECM interactions, impairing tissue architecture and function, particularly in vascular, bone, and skin tissues.
  • Fibrosis: Increased deposition of ECM components and activation of myofibroblasts, leading to pathological tissue stiffening and scarring 39.

Impaired Waste Clearance

Impaired waste clearance describes the age-related decline in the efficiency of systems responsible for removing metabolic byproducts, aggregated proteins, and cellular debris from tissues, particularly in the brain and other vital organs. This leads to the accumulation of toxic substances and contributes to neurodegeneration and organ dysfunction 40.

Beyond intracellular proteostasis and autophagy, organisms possess specialized systems for clearing extracellular waste. The glymphatic system in the brain, for instance, is crucial for removing metabolic waste products. The efficiency of these systems diminishes with age, leading to the buildup of detrimental substances that impair cellular and tissue function 41.

Mechanisms of Impaired Waste Clearance

  • Glymphatic System Dysfunction: Age-related decline in the efficiency of the glymphatic system, which facilitates the clearance of interstitial waste from the brain, leading to the accumulation of neurotoxic proteins like amyloid-beta and tau.
  • Lysosomal Storage Accumulation: Accumulation of undegradable material (e.g., lipofuscin, ceroid) within lysosomes due to impaired lysosomal function, contributing to cellular burden.
  • Reduced Phagocytic Activity: Decline in the efficiency of phagocytic cells (e.g., macrophages, microglia) to clear cellular debris, apoptotic cells, and aggregated proteins.
  • Vascular Impairment: Age-related changes in vascular integrity and blood flow can compromise the delivery of nutrients and the removal of waste products from tissues.
  • Extracellular Vesicle Overload: While extracellular vesicles mediate communication, an overload of dysfunctional or misfolded protein-carrying vesicles can overwhelm clearance mechanisms and spread pathology 42.

KI Gesundheits-Guide Hinweis – Die hier bereitgestellten Informationen dienen ausschließlich der wissenschaftlichen Kontextualisierung und Bildung. Sie stellen keine medizinische Diagnose, Therapieempfehlung oder Ersatz für professionelle medizinische Beratung dar. Konsultieren Sie stets qualifiziertes medizinisches Fachpersonal für gesundheitliche Anliegen.

Quellen & Weiterführende Literatur

Footnotes

  1. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1215. ↩

  2. Hoeijmakers, J. H. (2009). DNA damage, aging, and cancer. New England Journal of Medicine, 361(15), 1475-1485. ↩

  3. De Cecco, M., et al. (2019). L1 retrotransposition in the human brain and its implications for aging and neurodegeneration. Nature, 568(7752), 250-254. ↩

  4. Blackburn, E. H., Epel, E. S., & Lin, J. (2015). Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science, 350(6265), 1193-1198. ↩

  5. Shay, J. W., & Wright, W. E. (2019). Telomeres and telomerase: three decades of progress. Nature Reviews Genetics, 20(5), 299-309. ↩

  6. Bernardes de Jesus, B., & Blasco, M. A. (2012). Telomerase at the intersection of cancer and aging. Trends in Molecular Medicine, 18(3), 153-162. ↩

  7. Sen, P., & Adams, P. D. (2019). The epigenetic landscape of aging and cancer. Science, 364(6441), 648-652. ↩

  8. López-Otín, C., et al. (2023). The hallmarks of aging: 10 years on. Cell, 186(15), 3115-3149. ↩

  9. Pal, S., & Tyler, J. K. (2016). Epigenetics and aging: an intricate interplay. Science Advances, 2(7), e1600583. ↩

  10. Labbadia, J., & Morimoto, R. I. (2015). The biology of proteostasis in aging and disease. Annual Review of Biochemistry, 84, 435-464. ↩

  11. Hipp, M. S., Kasturi, P., & Hartl, F. U. (2019). The proteostasis network in health and disease. Annual Review of Biochemistry, 88, 415-444. ↩

  12. Vilchez, D., et al. (2014). Proteostasis and the aging genome. Trends in Cell Biology, 24(2), 104-112. ↩

  13. Fontana, L., & Partridge, L. (2015). Promoting longevity in real life: from yeast to humans. Cell, 161(1), 106-118. ↩

  14. Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of aging and age-related disease. Nature, 493(7432), 338-345. ↩

  15. Houtkooper, R. H., et al. (2012). The therapeutic potential of modulating NAD+ levels in metabolic disease. Nature Reviews Drug Discovery, 11(6), 455-468. ↩

  16. Sun, N., et al. (2016). Mitochondrial dysfunction and oxidative stress in aging and age-related diseases. Aging Cell, 15(1), 1-13. ↩

  17. López-Otín, C., et al. (2023). The hallmarks of aging: 10 years on. Cell, 186(15), 3115-3149. ↩

  18. Wallace, D. C. (2012). Mitochondria and cancer: Warburg effect revisited. Proceedings of the National Academy of Sciences, 109(32), 10147-10148. ↩

  19. Gorgoulis, V., et al. (2019). Cellular senescence: Defining a path forward. Cell, 179(4), 813-827. ↩

  20. Campisi, J., & d'Adda di Fagagna, F. (2007). Cellular senescence: when bad things happen to good cells. Nature Reviews Molecular Cell Biology, 8(9), 729-740. ↩

  21. López-Otín, C., et al. (2023). The hallmarks of aging: 10 years on. Cell, 186(15), 3115-3149. ↩

  22. Schultz, M. B., & Sinclair, D. A. (2016). Why cells age and why we should all care. Cell, 166(4), 804-808. ↩

  23. Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: the promise of youthful cells. Cell, 148(4), 621-625. ↩

  24. López-Otín, C., et al. (2023). The hallmarks of aging: 10 years on. Cell, 186(15), 3115-3149. ↩

  25. Franceschi, C., & Campisi, J. (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 69(Suppl_1), S4-S9. ↩

  26. López-Otín, C., et al. (2023). The hallmarks of aging: 10 years on. Cell, 186(15), 3115-3149. ↩

  27. Fafián-Labora, J. A., & O'Loghlen, A. (2020). How changes in the intercellular communication influence the aging process. FEBS Journal, 287(6), 1194-1202. ↩

  28. Fulop, T., et al. (2017). The role of immunosenescence in the development of age-related diseases. Reviews in Clinical Gerontology, 27(2), 174-184. ↩

  29. López-Otín, C., et al. (2023). The hallmarks of aging: 10 years on. Cell, 186(15), 3115-3149. ↩

  30. Franceschi, C., & Campisi, J. (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 69(Suppl_1), S4-S9. ↩

  31. Vaiserman, A. M., & Koliada, A. K. (2017). The role of the gut microbiota in the aging process. Experimental Gerontology, 94, 21-26. ↩

  32. López-Otín, C., et al. (2023). The hallmarks of aging: 10 years on. Cell, 186(15), 3115-3149. ↩

  33. Ragonnaud, E., & Biragyn, A. (2021). The gut microbiota-brain axis in aging and neurodegeneration. Immunology Letters, 236, 1-10. ↩

  34. Rubinsztein, D. C., et al. (2015). Autophagy and aging. Cell, 161(2), 224-235. ↩

  35. López-Otín, C., et al. (2023). The hallmarks of aging: 10 years on. Cell, 186(15), 3115-3149. ↩

  36. Levine, B., & Kroemer, G. (2019). Autophagy in the pathogenesis of disease. Cell, 176(1-2), 11-43. ↩

  37. Swift, J., et al. (2013). Nuclear lamin-A stiffness regulates mesenchymal stem cell differentiation. Science, 341(6146), 1240104. ↩

  38. López-Otín, C., et al. (2023). The hallmarks of aging: 10 years on. Cell, 186(15), 3115-3149. ↩

  39. Cox, T. R., & Erler, J. T. (2011). Remodeling the tumor microenvironment: new therapeutic targets. Nature Reviews Clinical Oncology, 8(11), 659-671. ↩

  40. Nedergaard, M., & Goldman, S. A. (2016). Glymphatic failure as a final common pathway to neurodegeneration. Science, 352(6281), aad9920. ↩

  41. Iliff, J. J., et al. (2012). A paravascular pathway for brain waste clearance: the glymphatic system. Journal of Clinical Investigation, 122(5), 1683-1693. ↩

  42. Tarasoff-Conway, J. M., et al. (2015). Clearance systems in the brain—implications for Alzheimer disease. Nature Reviews Neurology, 11(8), 437-450. ↩