BMH Medical Journal

BMH Med. J. 2020; 7(Suppl): Early Online. Geriatrics & Gerontology Initiative: International Workshop on Care of the Elderly

There is a progressive increase in longevity in the past few decades. Most of the time it is associated with decline in the quality of life. Main reasons for the longevity are due to better nutrition, better living conditions, better medical facilities and more importantly control of vaccine preventable communicable diseases which killed enmasse in the past.

Aging has its own inherent problems. Mitochondrial functions deteriorate, misfolded proteins accumulate and immune system becomes inefficient. As age advances there will be progressive accumulation of reactive oxygen species, inflammation increases at tissue level. There will be telomere erosion and regenerative capacity of the stem cells declines.

Incidence of cancer increases with age [1]. Aging is associated with telomere attrition and chromosomal aneuploidy. In a study done by Jochen B. Geigy et al [1] found that chromosomal instability index was twice in older fibroblast cells when compared to that of young cells. They also found that average length of telomere in old cells were only 50% when compared to young cells. Dysfunctional telomeres may cause anaphase bridges, dicentric chromosomes, chromosomal fragmentation, and non-reciprocal translocation. Their study identified 401 genes that were significantly differently regulated between young and old age groups which may be associated with age related aneuploidy, centromere and kinetochore function, microtubule and spindle assembly apparatus.

Current theories of aging

Current theories of aging are:

1. Programmed aging theory assumes the existence of a purposeful genetic program that determines the aging process.
2. The stochastic theory which suggest aging is driven by random accidental events that cause mutations and or regulations of cellular process. (Predrsgerceg et al in Journal of Genetics). In subgroup analysis they found that frequency of chromosomal aberrations was 9.3% in the age group 65 to 69, 6.8 % in 70 to 74 years, 6.7% in 70 to 75, 3.5 % in 80 to 84, 5.3% in 85 to 89 and 4.8% above 90 years. In younger age subgroups it was from 2.92% to 4.6%. The implication is those with lesser chromosomal aberrations live longer and healthier.
Changes associated with aging are genomic instability, telomere attrition. Epigenetic alteration, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication [2].

Genomic instability

There is progressive accumulation of genetic damage throughout life. This is by exogenous physical, chemical and biological agents and endogenous threat like DNA replication errors, hydrolytic reactions, and reactive oxygen species.

Mitochondrial DNA (mtDNA)

mtDNA has limited efficiency of repair and is under high oxidative stress. Most of these mutations originate in young age and it progressively accumulates as age advances. These changes lead on to respiratory chain dysfunction.

Telomere attrition

In humans there is a strong relation between short telomeres and mortality risk (Boonekamp etal; 2013). In old cells average telomere length was found to be 50% when compared to that of young cells [1].

Epigenetic changes

There is global hypomethylation and regional hypermethylation as age advances. The quality of air that we breathe could have an impact on methylation pattern [3]. Exposure to toxins, exercise, aspirin usage and smoking can have significant effects on DNA methylation. DNA hypomethylation can cause reduced genome stability and increasing chromosomal aberrations. Intake of essential nutrients like methionine, choline, folic acid and vitamin B₁₂ which are involved in one carbon metabolism may be important for healthy aging [4,5]. Epigenetic alterations are reversible.

Transcriptional errors

Aging is associated with transcriptional errors which lead on to aberrant production and maturation of mRNAs. This is associated with aging process and influences life span by targeting components of longevity network or stem cell behavior.

Loss of proteostasis

Misfolded proteins may accumulate in the cells of which structure has to be restored or they have to be degraded and removed from the cells. Otherwise cells will be dysfunctional and undergo apoptosis. This function gradually deteriorates as age advances.

Deregulated nutrient sensing

Deregulated nutrient sensing is the hall mark of aging and dietary restriction increases life span. This process is mediated through insulin and IGF-1 signaling pathway (IIS).

Cellular senescence

This is defined as a stable arrest of cell cycle coupled to stereotyped phenotypic changes. (Campisi and d’Adda di Fagagna 2007). This is a beneficiary response to damage so that damaged cells could be eliminated. It becomes deleterious when tissue regenerative capacity is exhausted. The process is mainly through telomere shortening and damage to non telomeric DNA.

Stem cell exhaustion

Haemopoiesis declines as age advances. Old haemopoietic stem cells undergo fewer cell divisions as compared to young ones. This can lead on immunosenscence and anemia. Same happens to most of the stem cell lines. Replacement old and damaged cells become slow or absent.

Altered intercellular communication

Aging involves alterations in inter cellular communication

There is a smoldering proinflammatory phenotype which accompanies aging which is called as inflammaging. Inflammaging results from accumulation of tissue damage, failure of immune system to effectively clear pathogens and dysfunctional cells, the propensity of senescent cells to secrete pro inflammatory cytokines, enhanced activation of NF-κB or occurrence of defective autophagy response (Salminen et al 2012). It leads to altered level of intercellular communication.

Restoring inter cellular communication

Restoration of defective intercellular communication in aging cells includes genetic, pharmacological or nutritional interventions. Calorie restriction extent healthy lifespan (Piper et al, 2011). Long term administration of aspirin may increase longevity. Gut microbiome shapes the function of host immune system and exerts systemic metabolic effects. It is possible to extend life span by manipulating composition and functionality of intestinal bacterial ecosystem of human body (Claesson et al., 2012, Ottavini et al ., 2011).

Chronological aging and biological aging may not go together. Even if it happens so, there is a gradual deterioration of all functions which makes people dependent at some time. Old people lose their hearing and vision. Then their ability to communicate decrease. The end result is that they become deafferented initially and deeffernted later. They need longer time to talk, eat and perform other daily activities. Care providers cannot find enough time for these always. This can lead on to emotional problems and frustrations. Most often care of the elderly is largely a social problem than medical issues. Researches are on to find a way towards healthy aging as health is the crux of the problem than the chronological age. Medical profession can treat only ailments. The results are not very satisfying in most cases.

Cellular And Genetic Changes In Aging