Cellular Aging Process Overview

Cell Ageing Process

• Cell ageing is a biological process that transforms a healthy, fit organism into one that is less healthy.
• This process is characterized by reduced tissue/physiological function, increased susceptibility to age-related diseases, and decreased resistance to physical and psychological stress.
• The molecular and physiological aging process, like IGF and p53 signaling pathways, are involved.
• Telomeres are associated with cellular aging.
• Cellular aging is a response to damage or stress. It leads to cell death (apoptosis) or arrested cell growth (cellular senescence).

Cellular Aging

• Cellular aging involves a balance between good and bad news. Good news is that it prevents cancer; bad news is that it promotes aging.
• The process of cellular aging is the body's response to damage and stress which leads to cell death (apoptosis).
• It can also lead to arrested cell growth (cell senescence).

Objectives

• Understand the molecular and cellular aging process, and its characteristics.
• Understand the molecular and physiological aging process, including signaling pathways (e.g., IGF and p53).
• Understand the connection between telomeres and cellular aging.

What is Aging?

• Aging transforms a healthy, fit organism into one that is less healthy, losing their vitality and fitness.

Aging is a Biological Process

• Aging is a process converting a healthy organism into a less healthy one, related to its environment.

Changes in the Plasma Membrane

• Structural changes in the plasma membrane lead to changes in permeability.
• Reduced membrane fluidity is due to a higher level of saturated fatty acids.

Nuclear Changes

• Chromatin becomes more condensed (more cross-links between histones), making DNA damage less likely to be repaired.
• This leads to cellular senescence.

Cytoplasmic Changes

• Cytoplasmic volume increases with age.
• Lipofuscin (age pigment) accumulates in non-dividing cells.
• This pigment is yellow-brown in color.

Mitochondrial Changes

• The number of folds (cristae) in mitochondria decreases.
• The number of mitochondria decreases.

Lysosomal Changes

• Lysosomal activity decreases, leading to the accumulation of cellular garbage (e.g., lipofuscin).
• Release of enzymes leads to cell death.

Pre-programmed Cell Death (Apoptosis)

• Apoptosis is different from necrosis, which is caused by external factors (trauma).
• Apoptosis is an internal process (cellular suicide) with non-random DNA breaks (180 base fragments).
• Apoptosis is a natural process of development, like the disappearance of interdigital tissue.

Cellular Aging Responses (Yin and Yang)

• Cellular responses to aging are a dual process.
• Good aspects prevent cancer; bad aspects promote aging.

Evolution of Long-Lived Organisms

• Cell division is risky!
• The lifespan of single-celled organisms is minimal.
• Longer lifespans occur in multi-cellular organisms, including post-mitotic tissues.

Cancer

• Cancer risk increases exponentially with age.
• (Somatic) mutations fuel cancer development.
• DNA damage, from both endogenous and exogenous sources, causes mutations.

Genes Involved in Cancer Protection

• Genes evolved to protect from cancer development (tumor suppressor genes)
• Damaged cells are caused to die or arrest growth due to tumor suppressor genes.
• This process is known as apoptosis or senescence.

Tumor Suppression and Aging

• A balancing act between protection from cancer and aging.

Senescence Morphology

• Senescent cells are flattened, enlarged with increased beta-galactosidase activity.
• Nucleus and nucleoli increase in size.
• Number of multinucleated cells increases, and the number of lysosomes, Golgi and cytoplasmic microfilaments increases.

Cellular Senescence

• Cellular senescence is the process of cell growth arrest in response to potential cancer-triggering events and DNA damage.
• Stress/damage signals and short/dysfunctional telomeres trigger senescence.
• Chromatin instability and oncogenes are other causes.

Molecules Secreted by Senescent Cells

• Senescent cells secrete molecules that disrupt normal tissue differentiation.
• Examples include milk production by mammary cells.

Cellular Senescence (Cellular Aging)

• Cellular senescence is cellular aging, involving a gradual change in cells shape and morphology from young to aged appearance.

Molecular & Physiological Mechanisms of Aging

• Dietary restriction after adulthood reduces the effects of aging and increases lifespan in various lab animals.
• Insulin/IGF-1 signaling pathway genes are implicated in aging because they regulate metabolism and stress responses, and affect maintenance functions.

Integrating Molecular Mechanisms with Life-History Theory

• Insulin/IGF-1 pathway regulates trade-offs between growth and maintenance.
• Poor environmental conditions, like dietary restriction, increase maintenance functions (survival) and decrease reproductive rates.
• Good environmental conditions increase growth and reproduction activities and decrease maintenance functions.
• Lab animal studies show that mutations in insulin/IGF-1 pathways do not lead to extended lifespans.

Role of Insulin-Like Signaling

• Is the role of insulin-like signaling evolutionarily conserved in various organisms, such as nematodes or flies?

Insulin-Like Pathway in Drosophila

• This pathway involves insulin-like ligands, receptors (DAF-2), and downstream signaling pathways, such as PI3K and AKT, culminating in increased longevity.
• Does it control aging? (Question)

Insulin/IGF-1 Signaling and Aging in Mammals

• Worms and flies have one insulin/IGF receptor.
• Mammals have insulin receptors, IGF-1 receptors, and insulin/receptor-like receptors.
• Mild reduction in IR gene function contributes to type 2 diabetes (non-insulin-dependent diabetes).

IGF-1, Insulin-like Growth Factor 1

• IGF-1 is a hormone that plays a role in cell survival, growth, puberty, and gonadal function, and reduced adiposity.

IGF-1 Receptor and Lifespan

• IGF -1 receptor regulates lifespan and resistance to oxidative stress in mice, according to Holzenberger (2002)

p53 Gene, Cancer Risk, and Aging in Mice

• p53 alleles affect mouse survival rates and rates of tumor development.

Telomeres and Aging

• A connection is hypothesized between the length of telomeres and aging.

What are Telomeres?

• Telomeres are repetitive DNA sequences at the ends of chromosomes.
• They contain thousands of repeating TTAGGG sequences.
• Humans have 92 telomeres (one on each end of each chromosome).

Telomerase and Senescence

• Telomerase levels in somatic cells are low. This leads to telomere shortening with each cell division.
• Short telomeres signal cells to stop dividing (senescence).

Telomerase and Cancer

• Telomerase is active in cancer cells.
• This allows cancer cells to maintain telomere length without shortening, resulting in immortality.

Short Telomeres and Growth Arrest

• Short telomeres can trigger growth arrest via p53 DNA damage checkpoints.

Tumor Cells and p53 Loss

• Tumor cells often lose p53 (the tumor suppressor gene).
• This loss of p53 leads to cell division without stopping at telomere checkpoints.
• This genomic instability promotes tumorigenesis (tumor development).

Telomere Function

• Telomeres protect chromosomes and separate one chromosome from another in the DNA sequence.
• Without them, chromosome ends are improperly "repaired". This leads to chromosome fusion and massive genomic instability.

Telomere Function (cont.)

• Telomeres act as a "clock", regulating cell division cycles. Telomeric sequences shorten with each DNA replication cycle.
• Telomere shortening causes cellular senescence.

Telomeres & Aging

• Healthy human cells have a finite cell division capacity, which decreases with age.
• Telomere shortening may be the molecular mechanism that counts cell divisions and triggers cellular senescence or growth arrest, leading to human aging.

How Does Telomerase Work?

• Telomerase is active in germ cells, immortalized cells (in vitro), the vast majority of cancer cells and, possibly in some stem cells.
• High telomerase activity is a defining characteristic of germ cells, stem cells, epidermal skin cells, and cancer cells.
• Immortal cells lack normal telomere shortening and have permanently active telomerase.
• Examples of immortal cells include cancer cells and some stem cells.

Human Aging

• The Greek myth of Tithonus illustrates the dilemma of living longer without maintaining youth.
• Living longer without maintaining youth is not ideal.

This quiz explores the biological concept of cellular aging, highlighting the physiological changes that occur as organisms age. Understand the molecular pathways like IGF and p53 that play a role, and learn about the balance between beneficial and detrimental effects of this process. Delve into the implications of telomeres and cellular responses to damage and stress.