unit 1 - genetics 677

What are the key takeaways from this graph?

• Average vs. Maximum Lifespan

• Average Lifespan ↑ in the last century, impacted by disease

• Maximum Lifespan, a measure of aging rate, has stayed stable, no ↑, determined by the rate of aging

Average Lifespan

• Average survival

• Impact by factors NOT directly related to aging

  • ex. mouse strains that are autoimmune disease prone will have a short average LS

Maximum lifespan

• Average survival of 1-% of animals that are longest lived

• Related to the rate of aging because of Goempertuz function

True or False: Mortality ↑ exponentially for most species

True

Goempertz function

• measures the ↑ in death rate that occurs with age.

  • If death is the consequence of aging = aging rate

  • e.g. chance of mortality doubles in 8 years for humans and 4 months for mice (25x)

  • The larger the doubling interval, the slower the aging process.

Reasons that longevity ↑ in the last century?

• Improvements in basic health parameters (sanitation and medical care reduce early death)

• Improvement in prevention and treatment of common diseases

  • Diabetes

  • Cardiovascular disease

  • High Blood Pressure

  • Last 15 years or so…cancer survival ↑

The Biological “Warranty Period”

Olshansky

• Human bodies have intrinsic biological expiration dates

• With AI or advanced medical tech to take out cancer or heart disease

• The fundamental systemic decay of cells, tissue, and brains will cause the body to naturally fail with a limit of 115 to 120 years.

Correlation between cancer and age?

• Cancer incidences increase dramatically with age but stop after age ~80

• Cancer is a major cause of mortality in the aged/middle-aged

• Preventing cancer only extends a human life by 3 years only

Limitations of longevity

• Longevity will increase and not continue to keep increasing because of…

  • control of cardiovascular disease

  • HBP medications

  • Antibiotics to cure bacterial disease

  • Diabetes control

  • Better prevention of infectious disease

  • Vaccines

• Intrinsic mechanisms (cells, organs, tissues) of aging have not been changed

Kidney function

• Example of the association between aging and physiological decline

• Low kidney functions, ↑ the risk of cardiovascular disease through toxin accumulation.

Sarcopenia

• Progressive and generalized skeletal muscle disorder involving loss of muscle mass and function

• Muscle strength decreases more than muscle mass

Multifactorial causes of sarcopenia

• Oxidative stress

• Changes in hormones, growth factors

• Neural plaque changes, motor neuron loss

• Mitochondrial dysfunction

• Satellite cell dysfunction

• Apoptosis

• Microvascular changes

• Inflammation

• Imbalance in protein metabolism

• Inactivity, disuse

What is this graph discussing?

Grip strength correlates with aging and longevity

What does this graph talk about

The prevalence of hearing loss

• Hearing loss also results in incident dementia

“Aging is associated with multiple, interacting tissue and organ "problems." What examples show this?

• Aging is associated with loss of kidney function, increasing cardiovascular risk

• Cardiovascular issues aggravate sarcopenia and some age-related hearing loss

• HBP increases the risk of cerebrovascular events

• Dementia risk, which may be impacted by cardiovascular disease and AHL, increases dramatically with age

How would slowing the aging process impact the human lifespan?

• We can increase life spans by 30%-38%.

Disposable Soma Concept

• The body is made of two types of cells, somatic and germ

• Male and female gametes form a zygot that generates embryo and later soma and gonads

• Germline is passed from generation to generation

• Same concept in a mouse

Evolutionary Considerations of Disposable Soma Concept

• The soma is mortal and disposable

• Germline is immortal and passed through generations

• Think about the selfish gene

• Aging may be due to progressive wear and tear processes in the soma that lead to the loss of cell and tissue function. Can be caused spontaneouslyactivities because of biochemical activitys that can slow the protective and repair mechanisms

• High predation: invest resources in early reproduction/offspring and NOT long life (e.g. rabbits, fish etc)

Would homo erectus invest resources in early reproduction/offspring?

Yes, because their lifespans reached 30 years of age because of violent lifestlyes and nutritional deprivation. It makes sense that they would have babies early on to continue life than foster investments in generating a slow aging soma.

What is the model prediction of impact of predation on the evolution of longevity

Opossums

• When they lived on predator-free islands, they reproduced later and aged slower than animals of the same species living on a hazardous inland

• High predation risks organisms evolve shorter lifespans, prioritizing early reproduction to maximize the chance of passing their genes down before being caught by prey.

Car Model Analogy

Ford Pinto

• poor reliability, bad parts, exploding gas tank

• Unlikely to have a long lifespan

Mercedes S Class

• Rbust, top quality parts, could last for ldecades

Lesson: in order to obtain long lasting soma, higher efforts are needed during construction and after.

Longevity Assurance Mechanisms (LAM)

• Systems that allow organisms to live longer and age slower

• Evolution of longvity involves multiple LAM

Antagonistic Pleiotropy Hypothesis of Aging

Medawar

• Pleiotropy is the phenomenon where a single gene influences 1+ phenotypic traits in an organism

• Antagonistic pleiotropy is when certain genes confer benefits early in the organism’s life, enhancing reproductive success and causing detrimental effects later in life and contributing to the aging process.

  • e.g. Mice homozygous for little spontaneous mutation are characterized by a deficiency in pituitary growth hormone (GH) along with prolactin and growth retardation. GH regulates IGF.

Are mammalian cells immortal?

Leonard Hayflick

• Performed experiments that showed cells could divide only a certain # of times in culture, the “Hayflick Limit” (40-60 divisions in humans)

• The number of cell divisions was specific to the species and appeared to correlate with lifespan

• Believed that aging is due to thermodynamics: entropy leads to accumulation of molecular damage (in proteins) and secondary effects such as aging phenotypes.

How can the Hayflick limit be overcome?

In human cells, the expression of telomerase can help

The hallmarks of aging

• Chronic inflammation

• Dysbiosis

• Genomic instability

• Telomere attrition

• Epigenetics alterations

• Loss of proteostasis

• Disabled macroautophagy

• Deregulated nutrient-sensing

• Mitochondrial dysfunction

• Cellular scenescene

• Stem cell exhaustion

• Altered intercellular communication

Yeast in chronological (CLS) and Replicative (RLS)

• Assymetrical cell division

• Mother cells can divide a finite # of times

Chronological lifespan methods

• survival in spent media, in pH buffered psent media, in water

Replicative lifespan methods

• microdissection, mother enrichment program, microfluidics

Limitations of the yeast aging model

• Low DNA methylation (~5% of mammalian levels)

• Single cell type (no tissues)

• Major replicative aging mechanisms (rRNA circles not relevant to human cells

Caloric restriction intervention

Metabolism impacts CLS yeast aging: with low glucose, less acetic acid produced