Fight Aging!

Aging is a collection of many varied forms of cell and tissue damage and forms of dysfunction in biological systems that all interact with one another as they progress. A cause can contribute to a consequence that in turn accelerates the cause. Except that in any narrow view there are likely another fifteen contributing causes and various consequences muddying the waters, making it challenging to assign relative importance to any one change or mechanism or interaction. Aging is a big ball of yarn, and there are only so many researchers and so much time. For any given mechanism or interaction, our understanding remains incomplete. Research into aging tends to focus on where the lamp presently shines, on the more well understood and well researched areas of cellular biochemistry and systemic dysfunction, but there is still a great deal that goes on elsewhere.

Today's open access paper is focused on a topic that doesn't come up all that often in the context of research into causes of aging. The authors are interested in the links between age-related changes in metabolism and the onset of frailty, a condition characterized by chronic inflammation, loss of muscle mass and strength, and loss of immune resilience. In the eyes of these researchers, evidence from clinical practice suggests that more attention should be given to metabolic acidosis in older people. This is a failure of metabolism to buffer against acidification of tissue environments. The chain of cause and consequence leading this outcome in aging is far from fully explored, as is the case for near all aspects of aging, but one can trace lines that lead from excessive acidosis to the various contributions to frailty.

Acid-Base Dysregulation Links Aging Metabolism to Frailty

For homeothermic humans, energetic efficiency is built on an optimal internal temperature and optimal pH, both of which are critical for maximizing enzymatic activity. Enzyme function underlies most biochemical reactions, including mitochondrial ATP production, the maintenance of membrane stability, membrane potential, and physiological performance. Overall, pH homeostasis at the intracellular and extracellular levels is preserved through complementary buffer systems and by regulation of cellular metabolism and activity, which are subject to both endocrine and behavioral control. Buffer systems such as the bicarbonate system provide the first line of defense against rapid pH fluctuations. Lungs respond within minutes by changes in ventilation, while the kidneys provide long-term regulation through excreting protons (H+) and generating new bicarbonate.

Accumulating epidemiologic evidence indicates that even "mild" deviations in serum bicarbonates have clinically meaningful implications for aging people. Observational studies have linked serum bicarbonate below 25 mEq/L - a threshold often considered clinically normal - to impaired physical performance, including slower gait speed, reduced muscle strength, and altered gait mechanics. Longitudinal data for initially well-functioning older adults (ages 70-79) further established low serum bicarbonate as an independent predictor of incident, persistent lower-extremity functional limitation. Notably, low bicarbonate level remains a significant risk factor for mortality even in individuals with preserved glomerular filtration rate (GFR > 60 mL/min/1.73 m2). The associations persist even with bicarbonate levels in the low-normal clinical range.

While lower bicarbonate levels are correlated with declining GFR, they also occur frequently in older adults with preserved renal function. In these cases, low bicarbonate plausibly reflects a mild or subclinical metabolic acidosis. The mechanistic association between acidosis and physical decline is thought to involve derangements in skeletal muscle metabolism that promote sarcopenia - the progressive loss of skeletal muscle mass, quality, and strength. These acidosis-induced derangements include catabolic signaling, insulin resistance, increased inflammatory cytokines, mitochondrial dysfunction, and oxidative stress, features that are also reported in the aging-related frailty phenotype. In comparison to aging, this catabolic process occurs more rapidly in chronic kidney disease (CKD) because of not only the greater severity of acidosis but also the accumulation of uremic toxins. Based on in vitro evidence, these toxins inhibit myogenic differentiation and damage mitochondria, further accelerating sarcopenia in CKD.

On this basis, it was proposed that acidosis-induced metabolic derangement in skeletal muscle also represents a key driver in aging-related frailty. However, it is critical to distinguish established mechanism from clinical hypothesis: while the cellular pathways are well-characterized in animal and CKD models, we lack longitudinal human data. Without tracking pH against frailty onset, it remains unclear if acidosis is a driver of frailty, a marker of its presence, or a consequence of muscle wasting (via loss of intracellular buffers).