Aging Mechanisms and Hallmarks

Historical Perspectives on Aging

  • Ancient Societies:

    • 5th century BCE: Herodotus mentioned the Fountain of Youth.

    • 400 BCE: Plato distinguished aging and disease.

    • Aristotle: Aging causes deterioration in mental function and is a natural disease.

    • Ancient Egyptians: Used garlic for healthy aging and longer lifespan.

    • 2nd-3rd century BCE: Chinese emperors took magic elixirs (often mercury based).

    • Alchemy: The search for immortality.

    • 1400s-1600s: Alchemists tried to rejuvenate the dead and develop pills for immortality.

  • The Search for the Fountain of Youth

    • 3rd century: Tales of Alexander the Great mentioned the Fountain of Youth.

    • 11th-12th century: Mythical king was said to rule over Asian.

    • 1513: Ponce de Leon searched for the Fountain of Youth in Florida.

    • 1550: Luigi Cornaro published "The Art of Living Long", emphasizing moderation and caloric restriction.

  • Early Theories and Discoveries:

    • 1860s: Alfred Russel Wallace - First Evolutionary Theory of Aging “Wear and Tear” theory of aging. Aging is necessary so that progeny have resources.

    • 1903: Ilya Mechnikov used the term gerontology and developed the concept of probiotics.

    • 1910-1930s: Scientists studied food restriction and lifespan.

    • 1900-1930s: Experiments on rejuvenation were conducted.

    • 1930s-1950s: Scientific societies focused on aging were established.

  • Modern Aging Research:

    • Since 1950, numerous hypotheses have been developed to explain aging.

    • Aging research has increased exponentially in the 21st century.

    • 2025: More than 20,000 papers already published in 2025 (PubMed).

Aging Population and Its Impacts

  • Worldwide Aging Population:

    • By 2030, 1 in 6 individuals worldwide is predicted to be over 60 years of age (more than 1.4 billion people).

    • By 2050, it is predicted that more than 2.1 billion people will be over 60, and the number of people over 80 is expected to triple to approximately 450 million.

  • Impacts:

    • Healthcare demands increase.

    • Potential slowdown in growth and productivity.

    • Shifts in family dynamics.

    • Housing adaptations are needed.

Defining and Studying Aging

  • What is Aging?

    • Aging involves time-related changes that lead to the deterioration of physiological functions.

    • Changes occur in gene expression, cellular function, molecular signaling, and sensory functions.

    • Systems regulation is altered.

  • How do we study aging?

    • Classic Model Systems: C. elegans (1 mm roundworm), Drosophila melanogaster (fruit fly), mouse and rat models, non-human primates.

    • Alternative models: mole rats, bats, sharks, clams, birds.

  • Exception to Aging:

    • Hydra (freshwater Cnidarian) can regenerate and do not appear to age.

Hallmarks of Aging

  • Key Hallmarks:

    • Nutrient sensing.

    • Epigenetics.

    • Genomic instability.

    • Genetic Predisposition

    • Mitochondria.

    • Stem Cell.

    • Proteostasis.

    • Cellular senescence.

    • Inflammation.

  • These mechanisms are interconnected, affecting the pace of aging and susceptibility to diseases.

  • The specific combination of coexisting diseases depends on genetic background and environmental/behavioral risk factors.

  • Multimorbidity is a major cause of disability, with the number of coexisting diseases being a strong risk factor.

Strata of Organismal Organization and Hallmarks of Aging

  • Strata of organismal organization

    • Meta-organism

    • Systemic circuitries

    • Organ systems

    • Organs

    • Supracellular units

    • Cells

    • Organelles

    • Molecules

  • Hallmarks of aging

    • Dysbiosis

    • Altered cellular communication

    • Deregulated nutrient-sensing

    • Disabled autophagy

    • Telomere attrition

    • Epigenetic alterations

    • Chronic inflammation

    • Stem cell exhaustion

    • Mitochondrial dysfunction

    • Genomic instability

    • Loss of proteostasis

  • Eroding hallmarks of health

    • Spatial compartmentalization

    • Integrity of barriers

    • Containment of perturbations

    • Maintenance of homeostasis

    • Recycling and turnover

    • Integration of circuitries

    • Senescence

    • Rhythmic oscillations

    • Responses to stress

    • Homeostatic resilience

    • Hormetic regulation

    • Repair and regeneration

Biology of Aging - Course Coverage

  • Major Topics:

    • Gene Regulation

    • Epigenetics

    • Cellular Changes (e.g., mitochondrial changes)

    • Molecular Changes

    • Physiological Changes

      • Cardiovascular

      • Metabolic

      • Muscular Changes

    • Frailty

    • System Level Impacts

    • Age-related diseases and disorders

    • Interventions

Hallmarks of Aging and Biological Age

  • Biological Age:

    • Refers to how old cells and tissues are.

  • Predictors of Biological Age (Table 1 Summary):

    • DNAmAge: DNA methylation (Mortality, frailty, cognition).

    • Telomere length: qPCR (Mortality, cancer, CVD).

    • Transcriptomic age: Gene expression (IL-6, urea, albumin).

    • Glycan age: Glycans, proteomics (Fibrinogen, HbA1c, BMI).

    • Protein-derived age: Proteomics (Low birth weight, Framingham risk score).

    • C-glyTrp: Metabolomics (Lung function, hip bone mineral density).

    • Metabolic age score: Metabolomics (Mortality, kidney function).

    • Composite biomarker: 10 biomarkers combined (Mortality, IQ, physical function).

    • Composite biomarker: 19 biomarkers in a clustering approach (Mortality, cancer, CVD, T2D).

Impact of Aging on the Genome and Gene Expression

  • Key Impacts:

    • DNA Damage

    • Genomic Instability

    • Telomere Length

    • Epigenetic Regulation

    • Gene Expression

DNA Structure and Organization

  • DNA Packaging:

    • DNA is organized into chromosomes within the nucleus of a cell.

    • The fundamental unit of DNA packaging is the nucleosome, consisting of DNA wrapped around histone proteins.

    • Genes are segments of DNA that contain the instructions for building proteins.

  • Components:

    • DNA consists of nucleotide base pairs: Guanine, Cytosine, Adenine, Thymine

DNA Transcription and Translation

  • Process Overview:

    • DNA undergoes transcription to produce pre-mRNA, which is then processed into mRNA.

    • mRNA is translated into a protein in the cytoplasm.

  • Key Steps:

    • Transcription: DNA is transcribed into pre-mRNA.

    • Translation: mRNA is translated into a protein with the help of tRNA and ribosomes.

  • Components:

    • Codons are triplets of nucleotides that specify amino acids.

DNA Damage

  • Causes:

    • Endogenous factors (e.g., reactive oxygen species, acetaldehyde production after alcohol consumption).

    • Exogenous factors (e.g., UV light).

  • Types:

    • Single-strand breaks

    • Double-strand breaks

    • Covalent bond cross-linking

    • Damage to inserted bases

  • Accumulation:

    • Somatic cells (non-germline cells) accumulate DNA damage daily.

DNA Damage Response

  • Outcomes:

    • DNA Repair: Multi-step process involving detection, removal, and resynthesis of DNA.

    • Cell Death: If repair fails, cell death mechanisms eliminate damaged cells (Apoptosis, Parthanatos).

    • Cell Senescence: Cells become unhealthy and lead to a pro-inflammatory state without cell death.

  • Mechanisms:

    • Apoptosis: Programmed cell death.

    • Parthanatos: DNA damage initiates program through PARP1, common in age-related neurodegenerative diseases.

    • DNA repair pathways correct DNA breaks.

Mammalian DNA Repair Pathways

  • Important for maintaining genome integrity

Genomic Instability

  • Definition:

    • Accumulation of mutations (alterations) in the DNA sequence, leading to permanent changes in gene expression.

    • Considered one of the hallmarks of aging.

  • Characteristics:

    • Changes may occur in protein-coding or non-coding regulatory regions.

    • Mutations can range from point mutations to chromosome rearrangements.

  • Mutation Rate:

    • Highest mutation rate: small and large intestine (~50 base substitutions per cell per year).

    • Lowest mutation rate: testis (~2.4 per year).

    • Neurons: ~16-21 mutations per cell per year.

    • Liver accumulates many mutations due to its role in detoxification.

Mutations at Single Nucleotides

  • Tissue Variation:

    • Different tissues exhibit varying rates of mutation accumulation with age.
      Rate of mutation accumulating mutations (SNVs/cell/year)

Telomere Length and Aging

  • Telomeres:

    • End sequences of chromosomes that protect chromosomal material from degradation.

    • Telomeres shorten each time a cell divides and replicates its DNA.

  • Telomerase:

    • The enzyme telomerase maintains telomere length.

    • Active in germ cells.

  • Impact of Aging:

    • Telomere length shortens with aging.

    • Ex: Human liver: loses ~55 base pairs of mean telomere length per year.

    • Shorter telomeres are associated with increased age-related diseases and decreased lifespan.

    • Increased telomere shortening increases biological aging and can increase genome instability and DNA damage.

Telomere Dysfunction and Age-Related Diseases

*The schematic representation of age-related diseases

  • AA, aplastic anaemia;

  • AD, Alzheimer's disease;

  • ALD, alcholic liver disease;

  • AMD, age-related macular degeneration;

  • CKD, chronic kidney disease;

  • COPD, chronic obstructive pulmonary disease;

  • IPF, idiopathic pulmonary fibrosis;

  • IRI, ischaemia-reperfusion injury;

  • MDS, myelodysplastic syndrome;

  • NAFLD, non-alcoholic fatty liver disease;

  • PBC, primary biliary cirrhosis;

  • PD, Parkinson's disease;

  • T2D, type 2 diabetes.

Telomere Shortening and Lifespan

  • Correlation:

    • Rate of telomere shortening correlates to lifespan across species.

  • Maximum Lifespan

  • Average Lifespan

Telomeres in the Naked Mole Rat

  • Naked mole rats live underground in colonies with a queen.

  • The Naked mole rats do not get cancer.

  • Naked mole rats has Very active DNA repair mechanisms and low mutation frequency.

  • They are Very long-lived (up to 30 years, compared to mice at 3 years).

  • Studies show few changes in gene expression in the brains of animals between 4 and 20 years old.

  • Telomere Length (34 kb) similar to humans (5 – 10 kb) – much shorter than mice or rats (50-150 kb).

  • Recent research shows better protection of telomeres in Naked Mole rat, so telomeres do not get shorter with aging – limits DNA damage.

  • 2023 Research in humans with a mutation allowing longer telomeres.

  • Longer Telomeres increase cancer risk in humans and mice rate of td. shortening is anindicator of cancer risk in the Naked Mole Rats.

Epigenetic Changes and Aging

  • Epigenetics Definition:

    • Modifications that change gene expression without altering the DNA sequence.

    • Can involve modifications to the DNA, histone proteins, or RNA.

  • Common Modifications:

    • DNA methylation

    • Histone acetylation

    • Histone methylation

    • RNA methylation

Examples of Epigenetic Modifications

*SUMO
*Ubiquitination
*Phosphorylation
*Biotinylation
*ADP-ribosylation
*Acetylation
*Methylation

Basic Structure of Genes

*DNA
*Promoter
*Transcription
*Splicing

DNA Methylation

  • Mechanism:

    • Methylation occurs at CpG sites (cytosine followed by a guanine).

    • Involves the addition of a methyl group CH3CH_3.

  • Effect:

    • Methylation usually silences gene expression.

  • Types:

    • Methylation at CpG islands.

    • Methylation at non-CpG islands.

Methylation Stops Gene Transcription

  • Mechanism:

    • Methylation prevents transcription machinery from accessing the DNA sequence.

  • CpG Methylation Impact on Transcriptional State

DNA Methylation Types

  • CpG Islands:

    • Areas of DNA where cytosine-guanine dinucleotides are at higher frequency.

    • Frequently in promoter regions (about 70%).

    • Usually greater than 200 base pairs in length with a G+C content greater than 50%.

    • Usually NOT methylated, enabling gene expression in promoter regions.

  • Methylation Levels:

    • About 80% of total CpGs are methylated in adults.

CpG Islands

  • CpG Islands:

    • CpG dense, usually unmethylated

  • CpG Islands Shores

    • Variable tissue- and disease-
      specific methylation, stronger
      regulators of expression.

Epigenetic Changes and Aging - The Epigenetic Clock

  • Definition:

    • Used to measure the age of tissues and cells based on changes in methylation.

    • Methylation acts as a biomarker.

  • Models:

    • Horvath’s model is most widely used (multiple tissues and cell types, across lifespan).

    • Tissue-specific clocks have also been modeled.

    • These clocks estimate age independently of telomere length.

Epigenetic Clocks

*Multi-tissue DNAm age estimator
*Single-tissue DNAm age estimator
*DNAm PhenoAge

Epigenetic Changes and Aging

  • Changes with Aging:

    • DNA methylation decreases at non-island CpG sites (hypomethylation).

    • Loss of DNA methylation increases genomic instability in repetitive DNA sequences due to retrotransposons.

    • Associated with age-related decrease in DNMT1 (DNA methyltransferase).

    • DNA methylation increases at CpG islands – represses (silences) gene transcription of specific genes.

Epigenetics and Aging

*Aging
*DNA methylation
*Transcriptional drift
Transposable element insertions
*Altered patterns of histone modifications

Transposable Elements

*Non-CpG island gene
*CpG island gene
*LINE
*SINE
*LTR
Transposable elements

The Epigenetic Clock

  • Influence of Lifestyle Factors:

    • Lifestyle factors can affect the epigenetic clock
      *Age Deceleration
      *Age Acceleration

Epigenetic Age Acceleration

*Weighted methylation average

Epigenetic Clock and Twin Studies

  • Twin Studies:

    • Monozygotic (identical) twins with the same DNA are studied.

    • Epigenetic markers and heritability: moderate to high (~50%).

  • Findings:

    • Over time, environmental factors contribute to differences in epigenetic markers.

    • Results in unique differences in aging even when individuals are older.

Summary of Biological Age Predictors

  • Predictor

  • Method

  • Studies, Age-associated outcome

Gene Expression and Aging

  • Measurement:

    • Impact on the genome of aging should affect gene expression.

    • Look at the RNA transcriptome to determine gene expression.

  • Methods:

    • Bulk RNA sequencing from tissues (hard to determine changes if the impact is only in a few cells).

    • Single-cell sequencing (tissue-specific studies in multiple organisms).