PHYSIOLOGICAL ADAPTATIONS THROUGH THE COURSE OF LIFE

Physiological Adaptations Through the Life Course

• Theme 3.1.1 explores physiological milestones, factors, and adaptations throughout the human lifespan, from intrauterine to old age.
• Specifically, it focuses on the regulation of human growth and development, intra- to extra-uterine transition, puberty/adolescence, and hallmarks of biological ageing.
• A compulsory knowledge check will be completed in real-time after the 4th lecture.

Phases of the Human Lifespan

• Prenatal (intra-uterine) phase is from conception to birth.
• Neonatal phase is from birth to 28 days.
• Infancy is from 1 month to 2 years.
• Childhood is from 3 years to 11 years.
• Puberty/Adolescence is from 12 years to 19-24 years.
• Adulthood includes prime and senescence phases.

Factors Regulating Human Growth and Development

• Hormonal Factors.
• Nutritional Factors.
• Environmental and Genetic Factors.
• Mechanical Factors (bone).

Human Growth Stages

• Fetal stage is where endocrine factors, including insulin and insulin-like growth factors, predominantly control growth.
• Infancy stage is where growth mainly depends on nutrition.
• Childhood stage is where the growth hormone-insulin-like growth factor-I (GH-IGF-I) axis and thyroid hormone are most important.
• Puberty stage is where activation of the hypothalamo-pituitary-gonadal axis to generate sex steroid secretion becomes vital for growth, along with the GH-IGF-I axis.
• Before puberty males grow taller than females.
• By 40 years of age, females increase more than males.

Hormonal Regulation of Growth and Development

• Adequate growth hormone is essential for children's growth.
• Thyroid hormones, insulin, and sex hormones (at puberty) have direct and permissive roles, which means their presence is required for other hormones to function.
• A deficiency in any of these hormones leads to abnormal growth and development.
• Hormones involved include growth hormone (GH), insulin-like growth factors (IGF-I and IGF-II), thyroid hormones (T3 / T4), insulin, and sex hormones (estrogen and androgens).
• Permissive roles involve one hormone exerting action in the presence of another, creating a symbiotic relationship, especially with growth hormone.

Growth Hormone and IGFs

• GH and IGFs are potent growth stimulators.
• The GHRH-GH-IGF axis is called the somatotropic axis
• Pulses of GHRH from the hypothalamus stimulate GH release, with the largest GHRH-GH pulse occurring during early sleep phases in adults.
• GH secretion occurs throughout life, but its biggest growth-promoting role is in children and a minor role in fetal growth.
• Excess GH before puberty leads to gigantism, while after puberty, it leads to acromegaly.
• GH deficiency before puberty results in stunted growth.
• IGFs are essential for fetal growth and have a postnatal growth-promoting role in children.
• IGF production in utero is independent of GH.
• Mutations of the IGF-I receptor gene result in severe intra-uterine growth retardation.

Thyroid Hormones

• Thyroid hormones regulate body metabolism, produce heat (thermogenic), and increase oxygen consumption.
• In the fetus, thyroid hormones promote normal growth, development, fetal maturation, and nervous system development.
• They are essential for bone growth.
• Thyroid hormone deficiency (cretinism) in infants leads to developmental delays, short stature, and decreased mental capacity if untreated promptly.
• Children with postnatally developed hypothyroidism experience slow bone and tissue growth, short stature, and often delayed puberty.

Growth - Soft Tissue and Bone

• Soft tissues include muscle, adipose tissue, connective tissue, fibrous tissue, and blood vessels.
• Soft tissue growth is controlled by GH, IGFs, thyroid hormones, and insulin.
• Both hypertrophy (cell growth) and hyperplasia (increase in cell number) are stimulated by these hormones.
• GH and IGFs are required for tissue protein synthesis and cell division.
• Insulin supports soft tissue growth by promoting protein synthesis and indirectly through energy from glucose oxidation, and plays a permissive role in GH function
• Bone growth is mainly influenced by GH and IGFs, with thyroid hormones playing a permissive role.
• Estrogen plays a key role in the adolescent growth spurt by stimulating bone growth via the GH-IGF axis
• Estrogen eventually induces the closure of epiphyseal plates.

Bone Growth Details

• The epiphyseal plate (growth plate) is where chondrocytes actively divide and produce cartilage.
• Cartilage cells harden to become osteocytes, forming bone that moves to the shaft ends, controlled by GH, IGFs, estrogen, and thyroid hormones.

Nutritional Factors in Growth and Development

• An adequate diet is essential for normal human growth and development.
• The diet should include protein, sufficient energy (caloric intake), vitamins, and minerals.
• Essential amino acids must be obtained from dietary sources.
• Calcium intake is critical for bone growth and formation.
• Preconception nutritional status of both parents affects the fitness of germ lines, influencing embryo and fetus growth and development.
• Maternal nutritional status is important for intra-uterine growth and fetal development Breastfeeding is important in postnatal and child growth and development.
• Malnutrition can delay childhood growth and permanently impact final adult height.
• Chronic malnutrition/undernutrition leads to GH resistance, increased circulating cortisol levels, and decreased thyroid hormone and sex hormone levels, resulting in slower growth.

Environmental and Genetic Factors in Growth and Development

• Stressful environments can cause "failure to thrive," marked by slow growth.
• Stressful environments include low socio-economic conditions, poverty, food shortage, societal and inter-personal violence, poor sanitation, air pollution exposure, and substance use.
• Cortisol from the adrenal cortex, released during stress, has catabolic effects that inhibit growth.
• Maternal substance use during pregnancy, such as smoking and alcohol, can lead to fetal alcohol spectrum disorder (FASD) and impact fetal and postnatal growth.
• Genetic factors determine an individual's potential adult size at conception.
• Adult stature is 70-90% genetically determined.
• Human stature is affected by genetic factors that influence epiphyseal growth plate function.

Mechanical Factors in Bone Growth

• Mechanical stress on bone is important for bone mass.
• Weight-bearing activities like running and walking help build bone (osteogenesis).
• Osteocytes and chondrocytes act as mechanosensors, transducing mechanical stimuli into intracellular signals for new bone formation.

Parent influences

• Puberty initiates reproductive life with functional gamete production.
• Pre-conception factors such as parental nutrition, obesity, substance use, stress, endocrine disruptors, and physical activity can influence gamete health.
• Post-conception maternal effects are directly mediated through the in utero environment, nutrition, and the maternal-infant relationship.
• Paternal influences develop postnatally through the paternal-infant relationship and risk exposures.
• Maternal and paternal health, behaviour, social, and economic circumstances indirectly affect offspring development in antenatal and postnatal phases.

Intra- to Extra-Uterine Transition

• The transition from the intra-uterine (fetus) to extra-uterine (neonate) environment is the most complex series of physiological adaptations in the entire human lifespan.
• The most striking adaptations occur in the lungs and circulatory systems.
• Prominent changes are observed in endocrine function, substrate metabolism, and thermogenesis.
• Physiological adaptations in the newborn can be complicated by modern medical interventions, such as caesarean sections, anaesthetics, analgesics, early umbilical cord clamping, and pre-term deliveries.

Essential Physiological Milestones

• Clearance of lung fluids
• Surfactant secretion and breathing
• Transition from fetal to neonatal circulation
• Decreased pulmonary vascular resistance
• Increased pulmonary perfusion
• Endocrine support of the transition

Aim of pulmonary adaptation in air breathing

• Clearance of lung fluid.
• Surfactant secretion.
• Air breathing

Clearance of Lung Fluid:

• The most important adaptation to birth is starting air breathing, however developing fetal airspaces are filled with fluid which impedes it.
• Lung fluid is transported and filtered by airway epithelial cells, containing a high chloride concentration due to active chloride uptake via Na-K-2Cl- cotransporters.
• Lung fluid production and maintenance are crucial for fetal lung growth, increasing around mid-gestation and peaking by late gestation.
• Clearance of lung fluid clears and commences just before labour to occur after delivery, mediated by cortisol, thyroid hormones, and catecholamines, responsible for Na+/K+/ATPase membrane transporter expressions in type 2 alveolar cells, creating an osmotic gradient for water removal from the airspaces.
• Subsequent clearance involves the newborn ventilating its lungs, pulling remaining fluid into alveoli, and later spontaneously transporting fluid into interstitial space.
• Preterm infants often cant clear lung fluid adequately due to a lack of Na+/K+/ATPase membrane transporters.

Surfactant and Breathing:

• Surfactant prevents alveoli from collapsing (“atelectasis”) during exhalation and promotes compliance (expansion during inhalation) because of a 'detergent-like' substance secretion containing protein, phospholipids and type ll alveolar cells.
• Surfactant secretion commences around the 22nd week of fetal development and stored until sufficient levels are reached weeks later
• This occurs mostly prior and upon delivery and helps prevent the inner alveoli from collapsing
• The key driving factor for surfactant is catecholomine levels
• At the 22nd week of development, production is stored in alveolar cells until sufficient levels reach week 34.
• Surfactant is released by type II cells before delivery, lining the inner alveoli walls to prevent expanding alveoli from collapsing.
• Stimuli for surfactant secretion involve increased catecholamine levels, binding to β-adrenergic receptors, increased ATP levels, and alveolar stretch with air ventilation

Fetal Breathing and Air Breathing

• In utero, the fetus exists in REM sleep and quiet sleep, with no clear periods of being awake.
• Fetal breathing activity only happens during REM sleep.
• Fetal breathing patterns involve variable volumes of fetal lung fluid flowing into and out of the lung. Fetal breathing is stimulated by high PO2, inhibited by hypoxia.
• Fetal breathing is needed to stimulate growht NOT gas exchange
• Purpose of fetal breathing is not for oxygenating the fetus but for fetal lung growth and developing breathing muscles.
• Air breathing is initiated primarily by umbilical cord clamping, reduction in maternal prostaglandin transfer, tactile, cold stimuli, and changes in blood Postmatally

Immature Lungs and Preterm Babies

• Preterm lungs are structurally and functionally immature.
• There is a low lung gas volume vs body weight ratio that results in low gas volume vs high metabolic demon ratio
• Functional residual lung capacity is already difficult enough to maintain
• Preterm babies are a huge risk of being structurally dysfunctional due to having a 'stiff lung' (low compliance lung)
• Require glucocorticoid in their treatment for lung mutation combined with a surfactant aeorosol to help treat the lungs more normally

Cardiovascular - Adapting the System

• Removing the placenta involves:
• Decrease in pulmonary vasular resistance results
• Oxygen transport now begins to require a great amount of cardiac output

Fetal Transport Vs Cardio

The combined system requires:

• 450mL/Kg/Min (R Ventricle accounts for 67%) and is what dictates the flow at this point in min Vs the system change with cardiac:
• Cardiac output doubles - and becomes the driving (but now the R ventricle only accounts for 50% with L accounting for the remaining 50%
• Organs with much higher requirement : Heart -> lungs - Kidney -> GIT

Factors For regulation

• Coritsol regulation
• Vaso Active hormones (Cortisol and Adh)
• RASS system
• Thymoid levels

Transition of Fetal Circulation

• The fetal system has the right heart more dominant to account for pumping blood into the aurta via ducts
• The baby does not rely on the right ventricle, so over time the heart transitions to the left side instead overtime
• increased left atrial volume is essential for increased functional closre for increased functionality
• The other shunt systems slowly shut off hours late due to: reduction in flow, increased pressure, increase atrial pressures

Changes in Energy

• Fetal energy relies on transport for everything but before birth stores glycogen and fat to prepare for demand
• insulin increase and glucagon decrease to prepare of pre-birth
• During birth they change and the body begins a slow and temporary fall in fetal fluids to compensate for damage via breakdown
• Thyroid increase
• All these lead to a thermogenistic effect

Hormal and Other regulation of childbirth

• Catacholamines - adrenaline increases, noradrelanie increase to prepare
• Surges of cotrsol induce
• Thyroid aids these things
• Lung fluids decrease
• Thermogenis increases
• Cateholamine and expression of B recptors increase
• Maturation of thryoid + functional MATURATion

9 Biggest Hallmarks of Aging

• Genetics and Genomic Instability
• Telomere attrition
• Epigeneric alteration
• Loss of protein
• Deregulate nutritients
• Mitochondrial disfinction
• Alters intercellular

Genetics and genomic instability

• Genetic causes of death = no one lives here The process of aging is genetically determined phenomenon in all humans, with the “ageing programme" and so-called "death clock" located in the DNA of chromosomes in cell nuclei

Telomere

Telomeres are "caps" - protect chromosome damage from degrading

• The very ends of the proteins are protected cycle by
• Telomere short till there's no telomee -> repectivse senescence

Big Four Systems of Decline

• Imparired protein homostaitsi
• Nutrietn Sensing

Mitochondrial and the ageing Body

mitochondrial function with leakage of electrons and resultant decreased ATP production, is an establishedcontributor to the ageing process excess mitochondrial ROS production can also promote accelerated ageing.