ageing

see also:

• androgen deficiency
• geriatrics
• longevity and immortality
• wikipedia

• the biologic factors causing mammalian aging process is still poorly understood
• aging is one of the most common risk factors for human disease

• the rate of ageing varies substantially across different species, and this is mainly genetically based and the biological mechanisms which regulate lifespan evolved several hundred million years ago
• genetic traits that benefit early survival and reproduction will be selected for in evolution even if they contribute to an earlier death
• ageing thus results from a combination of:
  • programmed genetic factors
  • acquired damage factors including injuries, wear and tear, environmental exposures, disease, free radicals, etc
    • epigenetic aging appears to increase with exposure to extreme heat days ¹⁾
    • inflammation
  • habit factors - to a certain extent, we become what our habits make us become
  • vicious cycles causing spiraling decline eg. damage may cause disabling injury which reduces mobility which reduces muscle mass and cardiovascular fitness and potentially causing obesity, all of which can contribute to cardiovascular disease, osteoporosis, frailty and cognitive decline
• suggested metabolic pathways:
  • the FOXO3/Sirtuin pathway, probably responsive to caloric restriction
  • the Growth hormone/Insulin-like growth factor 1 signalling pathway
  • the activity levels of the electron transport chain in mitochondria
    • studies have suggested a key role for decreasing NAD levels as a causative factor
      • taking eNAMPT from the blood of young mice and transferring it to older mice increased their life span by 16% and their life span correlated well with the serum levels of NAD
      • adipose tissues release eNAMPT into extracellular vesicles which are transported to the hypothalamus which then creates NAD and appears to be critical in the aging process ²⁾
  • the PTGS2/PGE2/EP4 pathway is required to induce and maintain the senescent phenotype of primary human keratinocytes (NHEKs), and that increased cellular PGE2 levels are a potential determinant of the initial steps of the age-related oncogenic process in skin cells ³⁾
  • reduced High Mobility Group Box 1 (ReHMGB1), a reduced form of a key extracellular senescence-associated secretory phenotype (SASP) factor, plays a critical role in transmitting senescence from aging cells to distant tissues. Senescent cells are known to secrete pro-inflammatory factors and signaling molecules-collectively known as SASP-which induce paracrine senescence in surrounding cells. ⁴⁾
• a 2024 study ⁵⁾ showed that in aging mice, the expression of IL-11 was upregulated in various types of cells and tissues and that the deletion of either the gene coding for IL-11 or the IL-11 receptor's alpha 1 subunit protected the mice against metabolic decline, frailty, and multimorbidity as they aged.
  • Furthermore, administering antibodies against IL-11 in mice aged 75 weeks and older for both sexes for 25 weeks improved muscle function, boosted metabolism, lowered aging biomarkers' levels, and reduced frailty. The deletion of the IL11 gene was found to extend the lifespan of the mice by an average of 24.9%, and treatment of 75-week-old mice with anti-IL-11 antibodies increased the median lifespan of male and female mice by 22.5% and 25%, respectively.
  • Additionally, given that mortality in mice due to old age is often cancer-related, it was observed that IL-11 inhibition significantly lowered the incidence of age-related cancers and tumorigenesis.
• a 2025 study in mice⁶⁾ showed that mice which lacked the gene which produces a protein called RGS14 live about 20% longer than normal mice, with females living longer than males – similar to the pattern seen in humans. Even at advanced ages, they maintain a healthier appearance, avoiding the typical signs of aging, such as loss of hair and graying that appear in normal elderly mice. Their brown adipose tissue also protects them from obesity, glucose intolerance, cardiovascular disorders, cancer and Alzheimer's disease, in addition to reduced exercise tolerance.
• the enzyme nitric oxide synthase (NOS), becomes less efficient as we age
  • this may contribute to hypertension and increased cardiovascular risk
  • specific oral bacteria (Prevotella living on human tongues) can enzymatically convert dietary nitrate (eg. beetroot juice and green leafy vegetables) to nitrite which is then converted to NO and may help replenish systemic NO levels.⁷⁾
• telomere length shortening as a sign of cellular ageing
  • telomeres are protective caps at the ends of chromosomes that get shorter as we age. When they become too short, cells lose the ability to divide properly, which can contribute to aging and age-related diseases.
  • it would appear that the central role played by C reactive protein (CRP) and the marginal role of antioxidants suggests that telomeres are particularly vulnerable not to oxidative stress, but to inflammation and this is more important than diet or exercise ⁸⁾

• ageing changes tend not to be linear but more exponential in their rate of change
• for each age group from birth to 85 yrs, males record more deaths than females each year in Australia

• peak youthful “beauty”
• peak fertility
• peak bone density
• often peak muscle bulk and strength but this is modifiable
• brain finally matures, usually by age 25
  • males in particular remain at very high risk of serious injuries due to immature risk taking behaviours
  • this period represents a hump in the general logarithmic mortality increases by age due to risk taking behaviours, and to a lesser extent, greater occupation hazards for males in particular
• atherosclerosis commences
• gradual loss of high frequency hearing perception commences

• declining fertility
• long term pregnancy-related changes
• declining “beauty of youth”
• generally declining peak physical performance and increasing soft tissue injury risks and long term damage
• brain cognition often peaks during this period but this is variable and perhaps modifiable
• lumbar and cervical disc degeneration commences in many and may present as disc prolapses

• atherosclerosis may become clinical, risk of acute coronary events in those who are predisposed (especially men)
• further ageing of skin, soft tissues and bone
• further decline in peak physical performance
  • most retire from elite sporting activities such as football, cricket
• auto-immune diseases become more common, especially for women

• women enter perimenopause and their risk of atherosclerotic diseases including acute coronary events increase significantly
• most people develop need for reading glasses
• further ageing of skin (solar damage becomes much more evident), soft tissues and bone, some develop osteoporosis, relatively inocuous injuries may cause significant issues such as Achilles tendon rupture, increased fracture risk from falls (especially in women)
• reduced respiratory reserve - some smokers will develop clinical emphysema
• reduced cardiovasculer reserve
• many develop hypertension, type 2 diabetes, etc
• increased risk of neoplastic diseases
• sudden cardiac death becomes a higher risk especially in men
• annual probability of death for Australians in 2024 in this age group is:
  • 45-49yrs: 0.17% ⁹⁾
  • 50-54yrs: 0.27%¹⁰⁾

• further, often rapid, progression of previous changes
• men may develop prostatism
• women are now nearly all in the post-menopause phase
• immune system becomes less effective, shingles and other infective issues become more common
• increased susceptibility to respiratory infections
• neoplastic disease, acute coronary events and strokes become much more common
• a period of accelerated and substantial limb muscle wasting unless active measures are taken to reduce this
• some will develop frailty and/or early onset dementia or other neurologic conditions
• primary osteoarthritis of PIPjts often commences at this time
• annual probability of death for Australians in this age group is:
  • 55-59yrs: 0.4%¹¹⁾
  • 60-64yrs: 0.6%¹²⁾
• overall the life expectancy for those reaching 65yrs of age in Australia is ~85yrs for men and ~88yrs for women ¹³⁾ (although long term effects of Covid-19 may have reduced this)

• most will retire from work
• many will buy caravans and become “grey nomads” until they reach 75yrs of age when their capacity to manage this declines too much
• much higher risk of diseases of ageing and further progression of disease risks of those in 55-65yr group
• some will develop end stage renal, respiratory or cardiac failure
• many will develop substantial hearing, visual or physical deficits and become increased falls risk as well as social isolation and depression risk
• annual probability of death for Australians in this age group is:
  • 65-69yrs: 0.9%¹⁴⁾
  • 70-74yrs: 1.5%¹⁵⁾

• many will still be able to function independently and for these holidays may become mainly cruises, being forced to give up their caravanning
• driving a car becomes increasingly dangerous and loss of independence is common
• many will need to transfer to assisted living arrangements
• further rapid progression of ageing
• annual probability of death for Australians in this age group is:
  • 75-79yrs: 2.6%¹⁶⁾
  • 80-84yrs: 4.9%¹⁷⁾

• women now outnumber men significantly and this age group and as a result, is the first age group that records more female deaths per year than male deaths in Australia¹⁸⁾
• annual probability of death for Australians in this age group is:
  • 85-89yrs: 9.3%¹⁹⁾
  • 90-94yrs: 16.6%²⁰⁾
  • 95-99yrs: 25.5%²¹⁾

• annual probability of death for Australians in 2024 in this age group is ~40-45% ²²⁾

• reduced hearing
  • this begins in teenage years with gradual loss of high frequency perception
  • presbycusis inhibiting speech perception occurs in over half of those over 75yrs - mammals have genetically lost the ability to regenerate cochlear sensorineural cells in the way that fish, amphibians and birds do
• reduced vision
  • presbyopia - inability to focus as close - this is most commonly evident from age 45yrs
  • over half of those over age 80yrs will have cataracts
  • macular degeneration is increasingly a problem in those over 80yrs
• osteoporosis
• atherosclerosis and primary prevention
• osteoarthritis
• reduced soft tissue collagen
  • skin
• thinning of skin epidermal layer
  • this may be able to be reversed by vitamin C ²³⁾
• reduced flexibility of joints
• reduced muscle mass, balance and coordination leading to frailty and falls
  • skeletal muscle mass decreases by 3-8% per decade after a person turns 30, and this deterioration accelerates after age 60
• UV induced skin ageing - keratoses, wrinkles, skin cancer
• graying of hair
• reduced cognition
  • peaks in mid-20's
  • dementia becomes more common with age
• reduced female fertility culminating in menopause
  • increases risk of osteoporosis, altered vaginal microbiota which then can act as a reservoir for pathogenic E.coli to cause recurrent cystitis²⁴⁾, etc
• reduced dentition
• increased DNA methylation levels
• increased risk of neoplasia / cancer / tumours
• increased risk of severe infections due to reduced immune system function
  • 5-15% of patients requiring admission to hospital from COVID-19 coronavirus (2019-nCoV / SARS-CoV-2) or influenza had impaired type 1 interferon responses due to the presence of autoantibodies that bind type 1 interferons (“neutralizing anti-IFN-I autoAbs”) - these occur in 2% of the population during their life time, usually at age 60-65yrs, and once developed are usually lifelong ²⁵⁾
• reduced respiratory capacity
• reduced cardiac capacity
• exocrine pancreas insufficiency (PEI) - this may lead to maldigestion and malnutrition
  • 5% of people older than 70 years and 10% older than 80 years have pancreatic exocrine insufficiency (PEI) with a faecal elastase-1 below 200 μg g−1 stool
• reduced liver size, functional capacity
  • decreased hepatic perfusion results in liver volume decreasing by 20–40% with age
  • those aged 65 years or older show an approximately 35% decrease in blood volume of the liver compared with the age group below 40 years
  • this causes an increase in the blood level of cholesterol, high-density lipoprotein cholesterol and neutral fat, whilst the metabolism of low-density lipoprotein cholesterol decreases by 35% while serum level of bilirubin gradually decreases and GGT and alkaline phosphatase levels increase
• reduced renal capacity
  • the number of glomeruli decreases at a rate of 6752 per year after the age of 18 years
  • the average kidney mass decreases from >400 g during the 3rd and 4th decade to <300 g by the 9th decade
  • age-related morphological changes are accompanied by functional losses: as the glomerular filtration rate and renal plasma flow of the kidney decrease with age, the diluting and concentrating capacities are reduced concomitantly
• reduced GIT function
  • resorptive capacity of the intestine also decreases with age due to reduced enzymatic capacity of the brush border, a reduction in the mucosal surface area in healthy elderly, and reduction in villus height
  • by age 75-80, 40% of people have a diminished ability to absorb food-bound vitamin B12 (cobalamin)
• increased risk of malnutrition due to:
  • reduced GIT function
  • reduced exocrine pancreatitic function
  • reduced liver capacity
  • poor food intake due to financial, mobility, cognitive, substance use (especially alcohol), or dental issues

• patterns of epigenetic markers
  • the pattern of methylation on retroelements seems to change as people age causing some genes to be more active which may lead to genomic instability, inflammation and age-related diseases
    • HIV infection accelerates epigenetic aging, while antiretroviral therapy appears to reverse the clock to some degree
    • The reactivation of specific retroelements increases with age, potentially leading to biological hallmarks of aging such as inflammation, cellular senescence and genomic instability
    • “Retro-Age” tool developed from machiine learning analyses of human endogenous retrovirus (HERV) and long interspersed nuclear element (LINEs) DNA retroelements ²⁶⁾
• somatic NUMTs (mitochondrial DNA segments which become embedded in neuronal DNA) can occur during a lifetime within neurons and fibroblasts, esp. the prefrontal cortex in response to cellular stress, and these seem to signal a shorter human lifespan and aging ²⁷⁾

• cells may undergo senescence (“senescence phenotype”) in response to DNA damage, which is associated with cell cycle arrest, altered gene expression and altered cell morphology
• this may be regulated by various mechanisms including:
  • protein palmitoylation
    • this seems to be reversed with 2-bromopalmitate (2-BP) - an inhibitor of protein acyltransferases ²⁸⁾

• healthy lifestyles which reduce frailty, cardiovascular, metabolic and cancer risks while improving mental health
  • see also: healthy living and diets
  • regular exercise
    • reduces risk of sarcopenia and osteoporosis as well as having cardiovascular, metabolic and mental health benefits
    • exercising muscles secrete cardiotrophin-like cytokine factor 1 (CLCF1) that plays a central role in mediating the health benefits of physical activity and helps strengthen both muscles and bones, thereby suppressing musculoskeletal aging - but in older adults you may need at least 12 weeks of continuous exercise regime to increase the secretion levels. CLCF1, a member of the interleukin-6 (IL-6) family, has been identified as a regulator of the glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFRβ) signaling pathway. It functions by binding to the ciliary neurotrophic factor receptor (CNTFR), promoting the recruitment and phosphorylation of gp130 and LIFR. CLCF1 plays several roles in development, motor neuron survival, immunomodulatory functions, and cancer. CLCF1 enhances mitochondrial function in muscle cells, inhibits the formation of bone-resorbing osteoclasts, and promotes the differentiation of bone-forming osteoblasts. Supplementation of CLCF1 improves muscle function and bone density in aged mice. ²⁹⁾
• prolonged fasting appears to prolong longevity
  • in animal studies, rapamycin had similar benefits to prolonged fasting but metformin didn't ³⁰⁾