What is aging?• Aging is the accumulation of changes in an organism or object over time. In humans,

aging is a dynamic process with physical, psychological and social dimensions.• The process of aging involves changes shared by all individuals (universal aging) and

others which merely become more common with age (probabilistic aging). • Senescence is the technical term for the process of aging. It refers to changes in an

organism’s biological functioning after maturity is reached and may occur on both a cellular and an organismal level.

• Rates of organismal senescence do not always correlate with chronological age, so functional age often varies as much within as it does between age groups.

Two Groups of Theories Regarding Senescence

• Stochastic (Damage-Based) Theories of Aging• Accumulated damage as a result of ongoing, imperfect biological

processes. – Free Radical Theory– DNA Damage Theory– Telomere Theory– Protein Cross-Linking Theory

• Programmed Theories of Aging• Changes in gene expression concerning repair enzymes,

hormonal levels, immune system function, etc.– Evolutionary Theory of Aging

Free-Radical Theory• When oxygen is used to make energy in human cells, it generates highly reactive compounds

known as free radicals or reactive oxygen species (ROS). Free radicals have an odd number of electrons and are therefore highly reactive, making them significant sources of oxidative stress. Antioxidant therapy is promoted by many as a means of combating the effects of free radicals.

DNA Damage Theory• Proponents of the DNA Damage theory of aging argue that aging results from the accumulated

mutations and errors in DNA sequences over the course of an organism’s lifespan. The theory explains that errors in the genetic code may lead to cancer, apoptosis, or cellular dysfunction.

Telomere Theory• Telomeres, sequences of nucleic acids located at the ends of chromosomes, are shortened during

each mitotic cell division. The telomere theory of aging suggests that the gradual shortening of our chromosomes is responsible for the cellular damage and dysfunction associated with aging. Telomerase, an enzyme found in germ and cancer cells, acts to restore the telomeres.

Protein Cross-Linking Theory (Glycosylation Theory)• The glycosylation theory of aging suggests that the aerobic binding of sugars to proteins impairs

protein function, leading to the inefficiencies in cellular function associated with aging. Protein Cross-Linking is encouraged by high blood glucose levels, so a diet with moderate to low intake of carbohydrates is recommended to avoid the theoretical aging effects of glycosylation.

Evolutionary Theory• Evolutionary theories of aging argue that the process of senescence is either not affected by

natural selection because it occurs after the peak of reproductive viability or it is selected for because it conserves resources for new generations, avoiding the problem of overpopulation. Hence, aging may actually be an adaptive feature of biological organisms based on a sort of biological clock, rather than an unfortunate and perpetual threat.

Genetics of Senescence• Research suggests a telomerase-based genetic clock may be located on the first

or fourth of the 23 homologous chromosome pairs found in humans. • Other genes that appear to affect the aging process include the Sirtuin gene

family (which code for Sir2 proteins), RAS genes, and GATA transcription factors. • Twin and adoption studies have suggested that genes account for an estimated

35% of an individual’s lifespan.

Maximum Human Lifespan• The maximum human lifespan is currently defined as 122 years and 164 days, as

set by a woman named Jeanne Calment. • The oldest man, Christian Mortensen, lived to 115 years and 252 days.• Men consistently have shorter lifespans than women, and this trend is apparent

in the life expectancies of nations across the globe. • Japan has the highest average life expectancy of any nation, with 78.0 years for

men and 86.1 years for women. • The United States ranks 36th for average life expectancy, with 75.6 years for men

and 80.8 years for women.

Historical Human LifespanEra Life Expectancy at Birth (years)

Upper Paleolithic 33

Neolithic 20

Bronze and Iron Age 26

Classical Greece 28

Classical Rome 28

Pre-Columbian North America 25-30

Medieval Islamic Caliphate 35+

Medieval Britain 30

Early Modern Britain 15-30

Early 20th Century 30-45

Current World Average 67.2

Unfortunately, such measures of average lifespan depend heavily on infant mortality and do not reflect the typical age of death for a fully grown adult. Also, contemporary methods of information collection may have varied enough among periods to produce significant discrepancies.

Blue Zones• Epidemiological research has revealed special regions called blue zones in which

people experience healthy, active lives for significantly longer than average. • Examples of these so-called longevity paradises include the island of Okinawa, Japan,

the mountain villages of Sardinia, Italy, the island of Icaria in Greece, the Californian city of Loma Linda, and the Nicoya Peninsula in Costa Rica.

• Common factors in these blue zone societies include regular yet moderate physical activity, social and familial engagement, a plant-based diet rich in legumes, no smoking, relatively few stressors, a period of the day reserved for decompression, and relatively low caloric consumption.

• Not only do these blue zones produce centenarians at a much higher rate than other societies, but they also experience a far lower incidence of disease, so their residents enjoy more healthy years of life.

Non-Human Longevity• The oldest known living organism is a bristlecone pine known

as Methuselah. Located in the White Mountains of eastern California, this tree is currently 4,844 years old.

• The Methuselah tree is named after the biblical Methuselah (Noah’s grandfather), who was the longest living person mentioned in the Hebrew Bible, at 969 years old.

• The animal with the longest verified lifespan was a quohog clam found on a seabed off the coast of Iceland, which was determined to be between 400 and 410 years old.

Biological Immortality• The Gompertz-Makeham law of mortality states that a death rate is a composite of age-

dependent and age-independent components. The age-dependent components, modeled by the Gompertz function, rise exponentially with age.

• Defined as the absence of cellular senescence, biological immortality implies a mortality rate that is not a function of chronological age.

• The Hayflick limit describes the maximum number of times a cell population can divide, which is believed to be related to telomere length. Many scientists believe telomere length acts as an inborn molecular clock for biological organisms.

• Certain animals, such as Tardigrades and Hydras, are believed to exemplify biological immortality because their cells do not appear to be subject to the Hayflick Limit.

• Other organisms, such as the bristlecone pine, quahog clam, and sea anemone, are said to exhibit negligible senescence, as they show very few signs of aging.

• Immortal cells (such as germ and stem cells) have their telomere lengths maintained by the telomerase enzyme, and activation of this enzyme can immortalize mortal cell lines.

• It is considered significant by many gerontologists that the cells of an organism typically demonstrate near perfect renewal during the peak years of the organism’s lifespan, which for humans typically falls between the ages of 20 and 35.

Tardigrade, colloquially known as a water bear A hydra, a member of the

phylum Cnidaria

• It is important to recognize that biological immortality may not be desirable for multi-cellular organisms because it may predispose an organism to cancer.

• As somatic cells continue to divide, the probability that they will contain mutated genes increases. Therefore, they would be of increased danger of becoming cancerous.

• A key factor in cancer cell proliferation is the activation of the telomerase enzyme by mutation, which allows the cell to divide indefinitely.

• Prevention of genomic instability is an important function for multi-cellular organisms, so aging may have evolved to protect against internal genetic drifts.

• Whether cellular senescence is directly related to aging on an organismal level is still a matter of scientific debate.

• In 2010, scientists were able to reverse the effects of aging in mice by activating a gene that stimulated telomerase production. This discovery is highly exciting for the scientific community, but the potential cancer risk and the transferability to humans remains a matter for speculation and experimentation.

Life Extension (Experimental Gerontology)

• Experimental gerontology is the field dedicated to expanding the maximum and average lifespan of human beings.

• Life extension has fascinated human beings throughout the course of history and is the topic of myths involving the fountain of youth, the holy grail, and the elixir of life.

• Although terms such as immortality and eternal life are often used to describe the ultimate goals of experimental gerontology, the correct scientific term is indefinite lifespans.

• The term indefinite lifespans lacks the religious connotations of the former two and does not imply a complete inability to die. An indefinite lifespan eliminates death as a biological inevitability, but does not protect an organism from death as a result of injuries or disease.

• Theoretically speaking, immortality and eternal life are physical impossibilities because of the second law of thermodynamics, the law of increasing entropy.

• Some life extensionists believe an indefinite human lifespan to be within the realm of scientific possibility, perhaps even for existing generations.

• Strategies for life extension may involve nanomedicine, caloric restriction, nutrition and supplementation, or genetic engineering.

Nanomedicine

• Theoretically, nanoparticles could eventually be used to facilitate or enhance basic physiological mechanisms.

• Nanomedicine is itself in its initial stages; therefore, the idea of using nanotechnology for physiological enhancement and lifespan extension is completely speculative.

• The intellectual and cultural movement which advocates the use of technology and science to transform the human condition by eliminating aging and enhancing physiological and psychological capabilities is known as transhumanism.

•Refers to the application of nanotechnology to medicine•Advanced drug delivery systems to allow for greater specificity and efficiency in pharmaceutical administration•Nano-electronic sensors to detect concentrations of biomolecules in real time•Nanosensors to communicate and interact with individual biological cells•Medical imaging visualization using luminescent tags known as quantum dots

Caloric Restriction With Adequate Nutrition

• Caloric restriction with proper nutrition is a means of enhancing lifespan by providing the body with only the nutrients which are necessary for its survival.

• Caloric restriction usually refers to limiting calories to 30-50% less than what a typical animal would consume ad libitum.

• Experimental and theoretical consensus supports the idea that the body, in semi-starvation mode activates pathways that reduce cellular damage and improve metabolic efficiency.

• Thus, by eating a diet rich in beneficial nutrients but which provides only slightly more than the calories needed to survive, the overall functioning of an organism may be improved.

• In experiments comparing caloric restriction to exercise, calorically restricted animals live significantly longer than exercised animals.

• Typically, caloric restriction only demonstrates significant effects when begun early in life. Moreover, some scientists believe its effects will be far less significant in long-lived humans as compared to short-lived animals such as rats.

• Overall, theories of caloric restriction are closely related to theories of metabolism.

• Some researchers have also argued that a high basal metabolic rate is inversely correlated with longevity.

• This idea is based on damage-accumulation theories of aging, since high levels of metabolic activity would produce more opportunities for cellular damage to occur.

• The suggested connection between metabolism and lifespan is known as the metabolic stability or rate of living hypothesis.

• The rate of living hypothesis enjoyed great popularity in the scientific community for some time because data appeared to link high metabolisms (as seen in small, active animals) with shorter lifespans when compared to larger, less metabolically active animals (such as humans or whales).

• However, the rate of living hypothesis has been undermined in more recent times by the observation that bats and birds, despite being small and metabolically active, live several times longer than rats, or other small animals with comparable metabolisms.

• Modern statistical analysis has also failed to adequately correlate metabolic activity with lifespan when phyletic relationships and more accurate biometric analyses are taken into account.

• The metabolic stability hypothesis stands on somewhat firmer scientific grounds, as it describes homeostatic metabolism as conducive to healthy aging. Thus, an organism with a stable metabolic rate, such as a human with a healthy BMI, is likely to live longer than a human who is over or underweight.

• Stress and disease are also regarded as significant metabolic disturbances.

Metabolism and Lifespan

Benefits• Reduction of total and LDL cholesterol

levels• Reduced tryglyceride levels• Improved HDL cholesterol levels• Reduced inflammation• Improved systolic and diastolic blood

pressure• Reduction of oxidative DNA damage• Improved fasting glucose and insulin

levels• Enhanced memory and neuroprotective

effects• Protects against diabetes, cancer, and

other major diseases• Improved body mass index• Increased average life span

Concerns• May cause musculoskeletal losses

(sarcopenia, osteoporosis, etc)*• May weaken the immune system • BMI below 18 associated with higher

mortality rates• May induce gluconeogenesis in

individuals with low levels of body fat• May not provide sufficient energy for

intense physical exercise• May hinder natural physical growth

in children or young adults (and is therefore contraindicated in individuals under 21)

• Excessive CR may result in starvation

* = Although reduced caloric consumption should theoretically reduce muscle mass and bone mineral density, experiments on CR animals have actually indicated increased muscle tissue and bone mass. No metabolic explanation for this phenomenon exists; however, some critics have suggested that CR animals enter a foraging state and simply exercise more than their ad libitum fed counterparts.

Nutrition and Supplementation• A variety of “superfoods” and supplements are marketed at consumers interested in

longevity. Some of the most common include:– Resveratrol, Metformin, DHEA (dehydroepiandrosterone), EGCG (epigallocatechin gallate), ALCAR,

CoQ-10, DHA, EPA, ALA, and a variety of vitamins and minerals. • As discussed earlier, a plant-based diet high in legumes and low in overall calorie value has

been associated with long life spans. • A some very recent studies have suggested many of the benefits of caloric restriction to result

primarily from the restriction of the amino acid methionine. • If this research is upheld, methionine-reduced foods could easily be produced such that the

benefits of caloric restriction could be easily be provided to the entire population. • It should also be noted that methionine is the first limiting amino acid in legumes.

Details on Longevity Supplements• Resveratrol - Found in red wine, grape skins, japanese knotweed, and other plants (where it is

produced in response to pathogenic infection), resveratrol is the the most heavily researched CR mimetic. In animals as diverse as fruit flies, nematodes, zebrafish, and rats, resveratrol has been seen to mimic many of the beneficial effects of CR. Nevertheless, Resveratrol has yet to be proven beneficial in primates, and some skepticism exists concerning the validity of existing research.

• DHEA (5-dehydroepiandrosterone) – Produced by the adrenal glands, kidneys, liver, and the brain, DHEA is the most abundant circulating steroid hormone in humans and is a precursor to the major sex hormones. In epidemiological studies, serum DHEA levels are a strong predictor of longevity in men. DHEA has also been found to have antidepressant effects, to lower evening cortisol concentrations. and to rise significantly in serum concentration during caloric restriction.

• Metformin – an antidiabetic drug used to reduce serum glucose levels, metformin has demonstrated effects similar to caloric restriction in laboratory animals and cell cultures.

• EGCG (epigallocatechin 3-gallate) – green tea extract, a potent antioxidant and the most abundant catechin in green and white teas. In black teas, EGCG is converted to thearubigins. Note: Consuming tea or tea extracts with milk may block beneficial effects as many tea molecules are rendered inactive when they bond to the casein protein in milk.

• ALCAR (Acetyl-L-Carnitine) – ALCAR is an acetylated, more bioavailable form of L-Carnitine, a potent antioxidant that plays a major role in fatty acid oxidation. ALCAR is believed to enhance energy metabolism, alleviate male infertility, encourage favorable body composition, improve glucose disposal, increase bone mineralization, and improve the function of neurotransmitters.

• Coenzyme Q10 (1,4-benzoquinone) – component of the electron transport chain and a potent antioxidant, CoQ-10 functions as an energy carrier in cells and is constantly oxidized and reduced. Its fully oxidized form is ubiquinone, its fully reduced form is ubiquinol, and its intermediate form is ubisemiquinone.

• DHA (docosahexaenoic acid) [22:6, n-3]* – an essential omega-3 fatty acid found in cold water fish and microalgae that is metabolized to form a class of signaling molecules known as the docosanoids. DHA is a major fatty acid in the brain, retina, and sperm cells. The increased consumption of DHA by humans is hypothesized by some scientists to have been responsible for the evolution of the modern human brain, which is uniquely large with respect to body size.

• EPA (eicosapentaenoic acid) [20:5, n-3] – an essential omega-3 polyunsaturated fatty acid which acts as a precursor to the eicosanoids. It is obtained in the human diet by consuming fish oil, and it is also an important component of breast milk. EPA shares many of the anti-inflammatory, anti-cancerous, neuroprotective, cardio-protective, and otherwise beneficial effects also associated with DHA.

• ALA (alpha linoleic acid) [18:3, n-3] – an essential polyunsaturated omega -3 fatty acid found in Chia, kiwifruit seeds, and flax (linseed). ALA, like DHA and EPA, is necessary to sustain human life because It cannot be biosynthesized de nono and must be attained through diet. ALA can be used as a precursor to DHA and EPA, but the process is extremely inefficient.

• ALA (alpha lipoic acid) – an antioxidant fatty acid often marketed as a weight loss or energy supplement, ALA appears to demonstrate numerous cytoprotective effects. ALA is a chiral molecule typically taken as a racemic mixture of its two enantiomers, RLA and SLA. ALA is said to act like a B vitamin at low doses but more like resveratrol when higher concentrations are used.

* = Fatty-acid nomenclature typically takes the form of [C:D, n-x], where C is the number of carbon atoms in the fatty-acid molecule, D refers to the number of double bonds, and x signifies the location of the first unsaturated carbon-carbon bond from the terminal methyl carbon. This nomenclature is preferred to the IUPAC names when describing fatty-acids because it provides greater denotative information in a more compact form (many of the properties of fatty-acids depend on the location of the first unsaturation relative to the terminal methyl group).

Genetic Engineering• Genetic engineering refers to the modification of an organism’s genome using DNA technology. • A genetically modified organism is one that is created by the introduction of recombinant DNA. This

DNA can be either foreign or synthetic. • Since the first genetically engineered organisms were genetically engineered in 1973, the field has

found applications throughout the realms of research, industry, agriculture, and medicine. • In 1982, bacteria were first bioengineered to produce human insulin for diabetics. Since then,

genetic engineering has allowed for the mass production of HGH, FSH, albumin, antibodies, blood clotting factors, fuels, vaccines, supplements, and a variety of other substances.

• In addition to creating organisms that produce human-specific molecules, genetic engineering has allowed for the creation of more appropriate animal models for fundamentally human diseases.

• Animals can also be genetically engineered to enhance animal-to-human transplantations. • Genetically modified food (GMO) is a major health and agricultural topic. Benefits of transgenic

organisms include improvements in growth rates, pest and disease resistance, improved crop yield, nutritional value, environmental tolerance, size, and aesthetic appeal. On the other hand, concerns have been raised about the potential health risks of GMO’s and about possible gene flow into unmodified organisms.

• In humans, genetic engineering has the potential to both eliminate genetic disorders and to improve overall physiological function.

“GloFish” were the first pet to be created through genetic engineering.

These mice have had their genes modified

to produce a desired fur

monocolor or mosaic.

• Negative genetic engineering (gene therapy)– Cures and treatments for genetic disorders– Non-pathogenic virus or other delivery system is used to insert the “correct” copy of

a gene into the genetic code of an individual. The inserted gene is proliferated through normal cell division.

– May be used to treat conditions such as CF, PKU, Sickle Cell Anemia, Hemophilia, and other genetic diseases.

• Positive genetic engineering– Enhancement of an organism or species– Questions what defines genetic “disorder” and suggests that curing and

enhancement only differ in their extent– Aging and death as medical conditions that may be resolved by genetic engineering.– Might allow “designer babies” and other optimizations of the human genome.

Human Genetic EngineeringForms:

What will perhaps one day be considered a primitive negative genetic engineering technique.

Techniques:

Human Genetic Engineering

• Somatic Engineering– Alters genetic information in non-reproductive cells.– Changes will only be expressed by cells altered during the

procedure. – Not inheritable; offspring will not display modified traits.

• Germline Engineering– Alters the genetic code for egg, sperm, or early embryonic cells.– Changes will be present in all cells of the organism.– Inheritable; modified genes will be passed on to subsequent

generations.

Gene Therapy: Major Historical Events

• September, 1990: first human gene therapy trials take place at the NIH– The trials are performed on a four year old girl named Ashanti DeSilva and a second, a nine year

old girl who chose to remain anonymous. – Both patients were afflicted with the genetic disease known as Severe Combined Immunodeficiency

(SCID). The form of SCID from which the patients suffered was an adenosine deaminase (ADA) deficiency, caused by the inheritance of two ineffective recessive alleles for the gene that codes for the enzyme. A lack of ADA leads to a buildup of adenosene that is toxic to B and T lymphocytes.

– The impressive positive response seen in DeSilva’s immune system after the procedure was a significant victory for the field of gene therapy and led to a flurry of research and funding in the field.

• Fall, 1999: University of Pennsylvania’s Institute for Human Gene Therapy begins a gene therapy trial for Ornithine Transcarbamylase (OTC) deficiency

– OTC deficiency is a X-linked recessive metabolic disorder involving the urea cycle caused by a mutation in the gene that codes for the OTC enzyme, which is vital to removing ammonia from the body

– On September 17, 1999, the death of Jesse Gelsinger leads the FDA to terminate all AD vector gene therapy trials while it reviewed the Gelsinger case.

– A variety of ethical and procedural violations were found in the Gelsinger gene therapy trials, and the FDA and NIH responded by instituting new, more stringent guidelines for future trials.

– The death of Jesse Gelsinger marked a major setback in gene therapy trials, as it called attention to the often unsuccessful and potentially fatal nature of the therapy.

Dr. James M. Wilson, whose academic misconduct led to the death of Jesse Gelsinger, still teaches as an honored

professor at the University of Pennsylvania.

Gene Therapy Procedure:

Four Phases of a Clinical Trial1. Apply for permission to try the experiment on human subjects.

a. FDA, NIH, RAC (Recombinant DNA Advisory Committee)b. 2-20 adult volunteersc. Informed consent

Subjects are given a range of doses, all of which are less than the highest dose given to experimental animals.

2. Results replicated with a larger number of subjects (100-300)

3. Drug tested on patients at a variety of research centersa. Most expensive phase of approval. Can cost millions (even billions) of dollars.

Typically requires backing from pharmaceutical or biotechnology companies.

If successful in phase III, the procedure is given formal approval for routine treatment.

4. Treatment is monitored for long term effects (~10-20 years)

Examples of Genetic Engineering Techniques• Plasma Method, commonly used for bacteria, in which a ring of DNA (a

plasmid) is placed in a container with the DNA sequence to be inserted. A specific restriction enzyme is then added which splices the DNA to form “sticky ends,” allowing the plasmid to combine with the desired gene. Bacteria that have incorporated the new gene can be isolated by comparing molecular weights or by measuring marker genes for antibiotic resistance or pigment production.

• Viral Vector Method, similar to the plasma method, uses a viral vector to insert DNA directly into the host chromosome using the enzyme reverse transcriptase. Viral vectors are currently the most effective means for administering human gene therapy.

• Biolistic or Gene-Gun Method, often used for engineering plant cells, involves firing pellets of DNA-coated metal (typically tungsten) into the cells of an organism.

• Human Artificial Chromosome, or an addition to the original 23 chromosomes, containing large quantities of manufactured DNA to be expressed by a cell.

Theoretical Applications for Positive Genetic Engineering

• Minimizing or reversing the aging process– Higher levels of HGH, telomerase, catalase, and other anti-aging factors – Repairing damaged DNA and proteins– Improving metabolic efficiency and sustainability

• Enhancing concentration, learning, and cognitions– Minimize the risk of mental disorder– Optimize potential for long-term potentiating and neural plasticity– Enhance glial cell myelination of axons

• Enhancing physiological function (musculoskeletal, cardiorespiratory, gastrointestinal, etc)– Replace iron with a more conductive metal (e.g. silver) in the human

respiratory chain– Replace hemoglobin molecules (porphyrin ring with four iron atoms) with

hemocyanin (two copper atoms bound as prosthetic groups) seen in arthropods for humans entering cold environments with low oxygen pressure (such as astronauts in space)

En Resumen• Approaches to extending human lifespan may take a stochastic or programmed

perspective on aging, and both genetic and environmental factors appear to play a role. • Most organisms seem to have a definite lifespan which is theorized to be set by a

biological clock, perhaps involving chromosomal telomeres and the Hayflick limit. • Common approaches to experimental gerontology include nanotechnology, nutrition and

supplementation, and genetic engineering. • Longevity evokes ethical questions involving the difference between treating debilitating

diseases and enhancing the basic functions of the human body. • Although numerous of life extension have

shown promise in laboratory studies, no means currently

exists by which the human lifespan can be expanded

indefinitely.

Things to Come• In the utopian visions held by the most optimistic and iconoclastic experimental

gerontologists, the methods addressed in this presentation, as well as others either not mentioned or not yet developed, will one day allow human beings to eliminate the thus-far perpetual problem of aging and death.

• Unfortunately, though average life expectancy continues to increase, its rate of increase is on the decline in many developed nations.

• Considering only current disease treatment methods, humans can expect only modest increases in average life expectancy. Medical specialists currently face an unwinnable battle as the rate of infirmity from any cause increases exponentially with age.

• Nevertheless, as this presentation should have made clear, confidence is growing among scientists that the ongoing scientific revolution will make humanity’s ultimate victory over age a legitimate possibility, perhaps even for existing generations.

• Whether it is through the elimination of a programmed biological clock, the practice of significant lifestyle modifications, or the mechanical, chemical, or genetic alteration of human physiological function, humankind can remain faithful to its dream that the omnipresent specter of death can perhaps one day be eliminated from its horizons.

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