My attention was drawn recently to an open access paper from earlier in the year that illustrates the magnitude of the difference between aging in early old age versus later old age. The causes of aging are comparatively simple forms of damage and disarray that emerge from the normal operation of metabolism, but because a living being is an immensely complicated system, even simple damage quickly spirals into complex consequences. Simple changes in a complex system produce complex outcomes. Aging greatly changes pace and character in its early stages versus its late stages, as chains of cause and consequence pile up, and damage interacts with damage. It accelerates, and dysfunction grows and changes in nature.
The work noted here looks at the transcriptome of aged mice, an assessment of which genes are being expressed, and to what degree. The differences between mice in early and late old age are sizable, and where it is understood as to what effects are produced by the differences in transcription, it connects to the usual concerns in aging: diminished function, increased inflammation, and so forth. This reflects what we see in our own species; there is a great deal of difference between a 60-year-old and an 80-year-old. The observed differences are built from changes in cell function, that emerge in response to rising levels of cell and tissue damage.
Different phases of aging in mouse old skeletal muscle
With a graying population and increasing longevity, it is important to identify life transitions in later years and recognize heterogeneity among older people. The term "late life" is broadly defined by encompassing a heterogeneous group of adults of 65 years and older; hence, it is further classified into "young-old" and "old-old" groups in the hope of identifying the group with a distinct vulnerability to certain chronic diseases and mental illnesses. Supportively, several studies have discerned a comprehensive difference across physical, cognitive, and psychosocial domains between the young-old (aged 60 - 74 years) and old-old (aged 75 years and older) groups. A similar distinction may exist for physiological and pathological domains, such as chronic illnesses (cardiovascular disease, cancer, chronic respiratory diseases, and diabetes, among others) and the deterioration of skeletal muscle and cognitive function. In reality, these age-related illnesses vary markedly and can, with age, take the shape of a comorbidity, which is the co-existence of two or more diseases. For instance, only 30% of adults aged 45 - 64 years have at least two chronic conditions, whereas 65% of those aged 65 - 84 years and approximately 80% of those aged 85 years and older have the same conditions. Therefore, to investigate these age-associated diseases, it may be beneficial to divide the elderly into groups and inspect the resultant subgroups separately for pathophysiological differences, and other deteriorations or weaknesses.
In the case of mice, those ranging from 18 to 24 months-of-age, which is comparable to humans of 56 - 69 years-of-age, fulfil the requirements of "young-old" age, whereas mice aged 26 months and older can be considered as "old-old". It is notable that 22 - 24 months of age is when morphological changes consistent with human sarcopenia commence in mice and rats. This is the period skeletal muscle mass and grip strength decline progressively with age, exhibiting prominent changes at 24-28 months of age, while whole-body mass and lean mass were relatively stable or only marginally declined. Another significant distinction between the young-old and old-old groups is survivorship; 24- and 28-month-old mice exhibit 85% and 50% survival rates, respectively. Based on this rapid declines in muscle mass and survivorship with age, we assumed that aging accelerates in "late life" in a manner different from that in the slow aging mode before then. In addition to the increased morbidity and accelerated aging, we recently noticed that skeletal muscle in old-old mice, but not in young-old mice, underwent DNA demethylation particularly over genomic retroelements, and as a consequence, a large number of genomic retroelement copies acquire the competence for transcription. Similarly, the existence of other unexplored molecular and physiological traits that distinguish old-old mice from young-old mice, is also conceivable.
Using 24- and 28-month-old mice to represent the "young-old" and "old-old", respectively, we compared their skeletal muscle transcriptomes and found each in a distinct stage: early/gradual (E-aging) and late/accelerated aging phase (L-aging). The old-old transcriptomes were largely disengaged from the forward transcriptomic trajectory generated in the younger-aged group, indicating a substantial change in gene expression profiles during L-aging. The divergence rate per month for the transcriptomes was the highest in L-aging, twice as fast as the rate in E-aging. Indeed, many of the L-aging genes were significantly altered in transcription, although the changes did not seem random but rather coordinated in a variety of functional gene sets. Of 2,707 genes transcriptionally altered during E-aging, two-thirds were also significantly changed during L-aging, to either downturning or upturning way. The downturn genes were related to mitochondrial function and translational gene sets, while the upturn genes were linked to inflammation-associated gene sets.
View the full article at FightAging
