week 11

• Primary Aging Processes


  • Deteriorative changes over time in the relative absence of disease or injury
  • Influence maximum life span
  • Thought to be the underlying cause of senescence across species
• Primary aging processes occur in the absence of disease
• Bill Collins: World's Fastest 50 Year Old


  • Age 17
  • Age 52
• Median Length of Life

  • Age at which there are as many individuals with shorter life spans as there are with longer ones
  • Protection from premature death underlie survival increases
  • Thought NOT to reflect primary aging processes
• Maximum Life Span


  • Age of the longest-lived survivors of a cohort or population
  • For humans, operationally considered to be the oldest age reached by 1 in 100 million people
  • Considered to be inversely proportional to the rate of aging of a population
• Prontosil


  The first commercially available antibiotic, a sulfonamide developed by the German biochemist Gerhard Domagk in the 1930s
• Penicillin


  • The first antibiotic, discovered by Alexander Fleming in 1928, but took over a decade before it was introduced as a treatment for bacterial infections
  • The introduction of penicillin marked the beginning of the "golden era" of antibiotics
• Antibiotics discovered and introduced to the market between 1940 and 1962


  • Most of the antibiotic classes we use as medicines today
• Life Expectancy: WHO 2019 - Top 20

  • Countries with the highest life expectancy
  • Japan, Switzerland, South Korea, Singapore, Spain, Cyprus, Australia, Italy, Norway
• Life Expectancy: WHO 2019 - last 24


  • Countries with the lowest life expectancy
  • Lesotho, Central African Republic, Somalia, Eswatini, Mozambique, Kiribati, Chad, Guinea-Bissau, Afrghanistan
• Longest-lived Humans


  • Jeanne Calment (France) Lived to age 122
  • Christian Mortensen (Danish-American) Lived to age 115
• Kane Tanaka


  Current oldest person, 118 years old, Japanese
• Places where people live the longest

  • Okinawa, Japan
  • Ovodda, Sardinia (Italy)
  • Loma Linda, CA (USA)
• Keys to longevity - Okinawa


  • "hara hachi bu" (eat until 80% full)
  • Rainbow diet (soy > fish, meat, eggs, dairy)
  • BMI 20.4
  • ~1200 cal diet
  • DHEA levels decline more slowly
• As many men live to 100 as women in Sardinia
• Keys to longevity - Ovodda, Sardinia


  • Descended from only a few original settlers - isolated, interbreeding
  • G6PD deficiency, other genetic traits?
• Keys to longevity - Loma Linda, CA


  • Seventh Day Adventists
  • Members live 5-10 years longer than fellow citizens
  • No drinking or smoking
  • Many adhere to a vegetarian diet
  • Spiritual life
  • Significantly lower levels of stress hormones
• Characteristics of aging


  • Increased mortality after maturation
  • Changes in biochemical composition of tissues
  • Progressive, deteriorative physiological changes
  • Decreased ability to adaptively respond to environmental changes
  • Increasing incidence of many diseases
• Exceptions to characteristics of aging

  • Increased mortality after maturation does not continue to increase exponentially at every advanced age
  • Changes in biochemical composition of tissues are quite heterogeneous from organ to organ and individual to individual
  • Progressive, deteriorative physiological changes (see above)
  • Decreased ability to adaptively respond to environmental changes (see above)
  • Increasing incidence of many diseases - elimination of atherosclerosis and cancer as cause of death would only add about 10 years to average life span and would not affect maximum life span potential
• Oxidative stress


  oxidants damage DNA, proteins and lipids

  • essentially an imbalance between production of free radicals and ability of body to constrict detoxify harmful effect through neutralization by antioxidants
• Genetic Basis of Aging Theories

  • High conservation of maximum life span between species
  • Similarity of attained age between monozygotic twins compared to dizygotic twins or non-twin siblings
  • Examples of exceptional longevity within families
  • Subsets of aging features in human genetic syndromes of premature aging
• Genetic cellular theories


  • Because a direct relationship exists between the life span of a species and the capacity of its cells to divide, this suggests that age related changes are programmed into the genes of each species
  • Aging is attributed to changes in DNA and RNA
• Evolutionary Theory


  • Risk of mortality increases with time after reproduction
  • Genes that confer early benefits on reproductive fitness are selected, even if they cause deleterious effects later in life
  • No selective pressure against genes that confer negative effects later in life
  • Strong pressure to retain genes that diminish vulnerability in young and old alike
• Replication Potential of Normal Human Cells


  • Soma --> post-miotic cells (no division); Quiescent replication-competent somatic cells (fine division); Stem cells (potentially unlimited cell division)
  • Germ line --> Primitive germ cells (eg. spermatogonia) - unlimited cell division
• Telomeres


  • Stretches of DNA at the ends of chromosomes that protect our genetic data and make it possible for cells to divide
  • Each time a cell divides, the telomeres get shorter
  • When telomeres get too short, the cell can no longer divide and becomes inactive or dies
  • Telomere shortening is associated with aging, cancer, and higher risk of death
• As a cell begins to become cancerous, it divides more often and its telomeres become very short
• Many cancers have shortened telomeres, including pancreatic, bone, prostate, bladder, lung, kidney, and head and neck
• Measuring telomerase


  • May be a way to detect cancer
  • If scientists can learn how to stop telomerase, they might be able to fight cancer by making cancer cells age and die
• Interventions in the Aging Process

  • Cell-based therapies
  • Hormonal therapies
  • Genetic manipulations
  • Dietary therapies
  • Other: hypothermia, exercise
• Caloric Restriction


  • Extends average and maximum life spans by 30-40% if initiated in early adulthood, and by 20% if started in early middle age
  • Usually 30-60% reduction in calories with adequate content of essential nutrients
  • Effect preserved in a variety of species, including rodents, fish, flies, and worms
• Caloric Restriction in Non-human Primates

  • 27 year old control
  • 27 year old CR
• Effects of Caloric Restriction in Non-human Primates

  • Lower body temperatures
  • Later sexual development
  • Later skeletal maturation
  • Lower weight
  • Less abdominal fat
• Common to both CR non-human primates & long-lived males

  • Lower levels of plasma insulin
  • Lower body temperature
  • Maintenance of higher plasma DHEA levels
• 25% CR in humans x 6 months
• DHEA


  • Dehydroepiandrosterone, a hormone produced by the adrenal glands, is a precursor to the sex hormones estrogen and testosterone
  • Blood levels of DHEA peak in one's twenties and then decline dramatically with age, decreasing to 20-30% of peak youthful levels between the ages of 70 and 80
• Antioxidant supplementation


  • Does not significantly change median or maximum life span
  • Except for vitamin E (and possibly vitamin C) being able to lower lipid oxidative damage, no evidence to support reduction in oxidative damage in humans
  • A compound with catalase and SOD activities extends longevity in nematodes
  • Foods with a high oxygen radical absorbance capacity may be more protective than other antioxidant preparations
  • Antioxidants may help reduce the incidence of age-related macular degeneration
• Hayflick: '"If the main goal of our biomedical research enterprises is to resolve causes of death, then every old person becomes a testimony to those successes. Biogerontologists have an obligation to emphasize that the goal of research on ageing is not to increase human longevity regardless of the consequences, but to increase active longevity free from disability and functional dependence"'
• Tosato et al., Clin Interv Aging. 2007 Sep; 2(3): 401–412.