Biology of Aging Quiz

Course Information

• Course title: Introductory Biology for Engineers
• Course code: SBL100
• Instructor: Archana Chugh
• Disclaimer: Slides developed using public domain sources for teaching purposes only

Aging and Immortal Cells

Aging? (The Biology of Senescence)

• Images of digitally painted age-progressed portraits of Dr. Sanjay Gupta.

Why do we get old? What is aging?

• Aging is phenotypic changes over time due to limiting processes.
• Aging is a biological process, not a disease.
• Aging converts a healthy organism into a less healthy organism.
• Are humans programmed to die?

Aging Features

• Aging = reduced functional tissue.
• Aging = increased susceptibility to age-related diseases.
• Aging = decreased resistance to stress (physical and mental).
• Aging = time-related deterioration of physiological functions necessary for survival.

Mortality in Aging and Non-aging Systems

• Graph showing risk of death over time for a non-aging system (e.g. radioactive decay) and an aging system.
• The non-aging system's risk of death stays constant over time.
• The aging system's risk of death increases over time.

Why do we age?

• Genes + Environment

Genes and Aging

• Genes determine species-specific lifespan.
• Genes determine differences in aging within a species (differences in gene expression / polymorphisms).

Species-specific longevity genes

• Flies (Drosophila melanogaster)
• Mice
• Humans
• Turtles
• Life spans range from 2 weeks to 200 years

Aging in Mice and Men

• Graph comparing aging processes in mice and humans.
• Mice age faster than humans.
• Humans are 90% genetically similar to mice

Species-specific longevity genes (Details)

• What are the genes that determine why mice live <4 years, whereas humans live ~80-100 years?
• Big pay-off, but complicated by development and the size of the genome to analyze.

Individual longevity genes

• Common to all members of a species.
• Small pay-off, but possibly amenable to intervention (environment, lifestyle, drugs).

Environment and Aging

• Present environment + Past environment

Present Environment and Aging

• Diet
• Exercise
• Stress

Diet and Aging

• Mitochondria - energy + ROS from oxygen
• ROS - damaging by-products that can modulate gene expression
• Anti-oxidant defenses are good but not perfect (vary among species).
• Optimal food = less ROS, less damage.
• Optimal food = longer lifespans.
• Realistic and sustainable nutrition

Exercise and Aging

• Exercise = greater fitness, healthier muscles
• Exercise = protection from oxidative stress
• Increased antioxidant defenses

Stress and Aging

• Physiological stress = hormonal changes.
• Physical stress (e.g., excessive exercise) = increased ROS.
• Mental stress = impaired cardiovascular function, reduced immune response, accelerated telomere shortening (e.g., parents caring for chronically ill children)
• Even perception of stress is correlated.

Past Environment and Aging

• Genes evolve in response to environment (a key factor in aging).

Aging and Past Environment

• Graph showing how the "protected" environment (climate control, biomedical intervention) and "natural" environment (hazards, climate, infection) affect human survival over time.
• Bad environment leads to accumulation of mutations that persist.
• Keep the environment good = extend lifespans, but it may take a very long time.

Primary, Antagonistic, and Integrative Hallmarks

• Diagram showing the relationship between primary, antagonistic, and integrative hallmarks of aging.

Plants

• Aging (Senescence) is a tightly regulated biological process.
• Plants have a highly complex genetic program for programmed aging.
• Plants have multiple layers of control for programmed aging.
• Leaf senescence.
• Autumn leaf colors of deciduous trees.
• Aging-senescence-death.

Hormones

• Hormones heavily influence leaf senescence.
• Abscisic acid
• Ethylene
• Annual vs. Biennials or perennials
• Programmed strategy
• Bamboo – monocarp - flower-set seeds and die (120 years).
• Fruit ripening.

Telomeres and Aging: Is there a connection?

What are telomeres?

• Telomeres are repetitive DNA sequences at the ends of human chromosomes
• They contain thousands of repeats of the six-nucleotide sequence (TTAGGG).
• Humans have 46 chromosomes and thus 92 telomeres.

Telomeres...

• Telomeres effectively cap the end of a chromosome, similar to plastic caps on shoelaces, protecting them from unraveling.
• Telomeric sequences shorten each time DNA replicates.

Telomere Shortening and Consequences

• Diagram showing telomere shortening leading to a loss of function, p53, cell cycle arrest, apoptosis, senescence, and genome instability.

Why are telomeres important?

• Telomeres allow cells to distinguish chromosome ends from broken DNA.
• Stop cell cycle! Repair or die!!
• Homologous recombination (error-free, but needs a nearby homologous chromosome).
• Non-homologous end joining (any time, but error-prone).

What do telomeres do?

• Protect chromosomes.
• Separate one chromosome from another in the DNA sequence.
• Without telomeres, chromosome ends would be "repaired," leading to chromosome fusion and massive genomic instability.
• Telomeres protect genome from degradation, unnecessary recombination, and interchromosomal fusion.
• Telomeres play a vital role in preserving information in our genome.

The End Replication Problem

• Diagram illustrating how DNA replication leaves 50-200 bp DNA unreplicated at the 3' end in each replication cycle.

Telomeres and Aging

• Telomeres are thought to be the "clock" that regulates how many times an individual cell can divide.
• Once telomere shrinks to a certain level, the cell can no longer divide, its metabolism slows down, it ages, and dies.
• Healthy human cells are mortal because they can divide only a finite number of times.

Telomere Length and Number of Doublings

• Graph showing a decline in telomere length with increasing cell division/doublings.
• Telomeres shorten from 10-20 kb to 3-5 kb after 50-60 doublings (in humans).

Telomeres & Aging

• Telomere shortening may be a molecular clock that counts the number of times a cell has divided.
• Shortened telomeres in dividing cells are responsible for some changes associated with normal aging.

What next?

• Scientists have determined a direct connection between telomere length and aging. What is the next step?

What is telomerase?

• Telomerase is an enzyme complex that's been called a cellular immortalizing enzyme.
• Telomerase stabilizes telomere length by adding hexameric (TTAGGG) repeats to the telomeric ends of the chromosomes. This compensates for telomere erosion.
• Cells in tissue culture with telomerase have extended telomere lengths and can divide for 250 generations beyond normal.

Telomerase Activity

• Most normal cells lack telomerase and lose telomeres with each division.
• High telomerase activity exists in germ cells, stem cells, epidermal skin cells, hair cells, and cancer cells.

Telomerase and Cancer

• Cancer cells do not age because they produce telomerase, keeping the telomere intact.
• Experimental evidence from hundreds of labs shows telomerase activity is present in almost all human tumors but not in adjacent tissues.

Telomerase (Details)

• Predicted by a Soviet scientist.
• Discovered by Greider and Blackburn.
• Found in ciliate protozoa (Tetrahymena thermophiles).
• 2009 Nobel Prize in medicine or physiology.
• Is a reverse transcriptase that carries its own RNA.

Telomeric DNA

• Diagram showing telomeric DNA in normal and cancerous somatic cells.
• Normal cells shorten telomeres with each division and eventually have cell division arrest.
• Tumor cells have telomerase activity and show continuous elongation and immortal growth.

Hayflick Limit

• The number of times normal cells divide before stopping.
• Telomere shortening determines the Hayflick limit.

Werner Syndrome

• Shows accelerated aging due to rapid telomere shortening.
• Werner syndrome patients experience symptoms including cataracts, skin ulcers, type 2 diabetes, etc.

Aging Suppressor Gene/Klotho Gene

• Identified by Kuro-o et al in 1997, named Klotho.
• In Greek mythology, Klotho spins the thread of life.
• Present in humans as alpha Klotho, a multifunctional protein regulating metabolism of phosphate, calcium, and vitamin D.
• Highly conserved sequence, 98% identical between humans and mice. Levels of klotho decrease with age
• Deficiency of alpha Klotho is linked to chronic kidney disease, malfunctioning, shorter lifespan, and premature aging.

Issues with Immortality

• Socio-ethical acceptance
• Readiness with resources for human population

Issues with Immortality (Details)

• Socio-ethical considerations.
• Resource availability for the human population.
• Ethical and economic issues with health and functional capacities.
• Health and functional capacities.
• Participation within society.
• UN/WHO concerns as a global issue.

Immortal Cell Lines (HeLa cells)

• In 1951, a scientist at Johns Hopkins Hospital created the first immortal human cell line (HeLa cells) from a cervical cancer patient's tissue sample.
• HeLa cells have been invaluable to medical research.
• Patient's identity remained a mystery for decades.

Laboratory-grown human cells

• Used to study cell function, test theories.
• Used to cause and treat diseases.

Immortal Cell Lines

• Can grow indefinitely, frozen for decades, divided into batches.
• Shared among scientists.

Landmarks using HeLa Cells

• Developing the polio vaccine.
• First space missions to see how cells respond to zero gravity.
• Cloning, gene mapping, in vitro fertilization.
• First human biological material to be sold/bought (multibillion dollar industry).

Possible Interventions to Delay Aging

• Stem cells (embryonic, adult, nuclear transplant).
• Anti-oxidants
• Telomerase

Drug-based therapies

• Anti-oxidants, mitochondrial protectors, etc.
• Hormones (growth hormone, insulin/IGF, estrogen).
• CR mimetics.

Relation between Calorie Restriction (CR) and Aging?

• Decreasing nutrient intake without malnutrition can increase health and lifespan.
• Reported in numerous organisms, including humans.

Calorie Restriction Mimetics (CRM)

• Many naturally occurring compounds in our diet (nutraceuticals) may act as CRM.

CR and the Four Hypotheses of Aging

• Diagram exploring the relationship between CR and hypotheses of aging.
• Four different hypotheses for the causal mechanisms and strategies leading to aging.

Test your knowledge on the biological aspects of aging. This quiz covers key features of aging, the distinction between aging and disease, and how resilience to stress affects aging systems. Challenge yourself with questions that delve into the mechanisms behind the aging process.