Current Aging Science (v.9, #2)

Meet Our Editorial Board Member by Marios Kyriazis (79-80).

There is no doubt that the world is divided and unequal, mostly with respect to wealth. However, the true obstacle preventing the progress of humanity is not the divide between the rich and the poor. It is the divide between the cognitive and the physical. Apart from the social and ethical issues associated with this, there are also medical ones. The implications of this divide have direct relevance to aging, both in research and in the clinical sense. We cannot simply apply the same 'healthy aging' guidelines to everybody, but we need to establish if our approach is specifically suited to the individual. Our research endeavours need to have this division in focus. In this Opinion paper I describe three separate groups of humanity, which are divided, not by economic criteria, but by a worldview of intellectual creativity. Each arbitrary group has its own health priorities. If we overlook these priorities we may, at best, give the wrong advice to our patients, or at worst waste resources and exacerbate the rate of age-related degeneration in many individuals. As our society becomes more reliant on technology, what is now considered 'healthy' may not be so, for many millions of people.

It is proposed that a primary and fundamental aspect of metazoan evolution is an ability to control and extend the longevity of individual cells. This was achieved through an intracellular oscillator, dubbed 'Life's Timekeeper', which evolved in the hypothetical ancestor of all metazoans. Slower oscillatory frequencies directed metazoan evolution towards extended longevity of individual cells, enabling generation of many specialised types of terminally differentiated cells. As the longevity of these cells was still relatively short in more primitive metazoans, stem cells, capable of differentiating into all specialised cell types, were retained in order to replace senescent cells. With increasing cell longevity, continual replacement of all senescent cells was no longer necessary. Cells such as neurons could be sustained throughout life, enabling the evolution of brains, hence, complex behaviour and intelligence. In multicellular metazoans the oscillator remains synchronised across all cells. It coordinates the timing of all cell-cell signalling systems, hence controls the timing of development and aging/senescence. In advanced metazoans, where senescent cells are not continually replaced, it controls lifespan. With regards to morphological evolution the oscillator, through alterations to developmental timing, controls change in size and shape. With regards to life history theory it functions as the key variable mediating the correlation between life history traits. This theory is compatible with a prominent role for environmental selection but, as it implicates some degree of internal mediation and direction, it is not entirely compatible with the 'modern synthesis' view of natural selection.

Background: Aging can be defined as the time-related decline in biological functions which ultimately results in organismal death. Beyond the stage of reproductive maturity as fertility declines, cell and tissue functions come under reduced selection pressure since organismal survival is considered no longer an evolutionary priority. Repair mechanisms become less robust and the resulting stochastic accumulation of tissue and genomic damage is believed to underlie the aging process. The objective of this review is to challenge this construct and to present evidence that aging represents a species-specific adaptive developmental program.

Methods: Through a review of published data, the cellular aging programs of both single cell and multicellular organisms are described. Since all organisms live in communities (ecosystems) of diverse species, the role of multi-level selection is discussed within this context and a proposal is advanced that aging represents an adaptive phenotype.

Results: Single cell organisms evolved an aging phenotype in which the primary feature was replicative arrest prior to cell death. The evolution of multicellularity represented the emergence of a new level of biological organization. Multicellularity required cell-cell cooperation as well as a division of labor. In simple multicellular organisms aging was rooted in an age-related decline in stem cell function (renewal and differentiation). In complex multicellular organisms cellular aging/ death programs (senescence, autophagy, apoptosis) were used as a form of cell “altruistic” suicide carried out for the benefit of the whole organism (morphogenesis, tissue repair and maintenance). Organisms do not live in isolation. Species occupy ecological niches and communities of diverse species comprise an ecosystem. Ecosystems are highly regulated and structured biological organizations. The effective functioning and productivity of an ecosystem is determined by its biological diversity and relative species densities. Multilevel selection acts to balance optimal functioning of both the whole ecosystem and its compositional species/organisms.

Conclusions: Organismal aging and death programs are adaptive; these programs provide a mechanism for regulating species population densities within the constraints imposed by the ecosystem organization. A unique feature of humans has been the development of a second inheritance system, culture. Through cultural practices, humans have expanded our ecological niche to be global in size. Our technology enriched urban ecosystem is very different from natural ecosystems. Our future evolution, including aging and lifespan, will be determined by our unique urban ecosystem through geneculture co-evolution.

Anesthesia Issues in Central Nervous System Disorders by Pravat K Mandal, Sumiti Saharan, Olivia Penna, Vincenzo Fodale (116-143).
Every year, millions of people affected by disorders of the central nervous system (CNS) undergo various diagnostic, therapeutic and surgical procedures requiring administration of anesthetic agents. Anesthetics exert their anesthetic, amnesic and analgesic effects by acting on multiple neuronal membrane proteins in the CNS. While some of the causal anesthetic targets have been identified, a large number of anesthetic targets remain unknown. The consequent longterm effect of anesthetic agents on expression of these various molecular targets has been implicated in mediating potentially long-lasting adverse effects. Recent work suggested that the effects of general anesthetics may not be entirely reversible, with animal studies demonstrating persistent changes in CNS protein expression post recovery from anesthesia. Age-associated or disease-induced alterations in the CNS can profoundly alter multiple aspects of brain structure, biochemistry, and function. Such maladaptive changes in the brain can render it increasingly vulnerable to the effects of various anesthetics. The selection of appropriate anesthesia drugs and protocol is mandatory, especially in individuals with pre-existing CNS disorders, so as to maximize anesthesia efficiency, avoid occurrence of adverse events, and ensure patient safety. This review aims to summarize and consider the effects and potential risks of commonly used anesthetic agents in patients with compromised CNS function. We provide a comprehensive review of the established as well as the implicated effects of anesthetic agents on the elderly as well as on the pathology and progression of common neurological conditions.

Promoting Cognitive Flexibility Under Attention-demanding Conditions in Aged Rats by Christine T. Kozikowski, Joshua A. Burk (144-149).
Background: Age-related decline in cognitive flexibility and learning contributes to poorer quality of life. Thus, it is important to develop procedures that minimize age-related cognitive decline. Previous research has shown that, when young adult rats were trained in an attention-demanding task with a distracter, they learned a new task more quickly compared with rats trained in the same attention- demanding task without a distracter.

Objective: The goal of the present experiment was to test whether this beneficial effect of distracter exposure was observed in aged rats.

Method: Male FBNF hybrid rats (n=20) trained in a two-lever visual sustained attention task that required discrimination of brief illumination of a centrally located panel light compared with trials when the light was not illuminated. At age 20 months, half of the animals received a flashing houselight distracter for the remaining testing sessions and the other animals did not. After 20 sessions, new task trials were interspersed within the sessions, when the rats received water access for pressing the lever under the left or right panel light after that light was illuminated.

Results: When 70% of the trials in a session were the new discrimination task, the distracter-exposed animals had higher accuracy in detecting the shortest signal in the remaining attention task trials compared with rats not exposed to the distracter.
Conclusion: The present results suggest that aged animals' learning can benefit from overcoming distracter exposure, although not to the same extent as younger animals.

Background: Polypharmacy is a key problem for those ?65.
Objective: To summarise for individuals ?65 the rates of Potentially Inappropriate Medications (PIMs) identified by application of STOPP, and Potential Prescribing Omissions (PPOs) by START criteria.

Methods: Search: Databases were searched 1980 to 1 December 2015. For Medline the search yielded 3,691 systematic reviews or meta-analyses and 301 when limited to 65 years and over. yielded 180 citations, 109,132 and 105 when limited to both. For Embase the search yielded 24,681 systematic reviews or meta-analyses, and 881 when limited to 65+ years. yielded 427 citations and 147,322, and 327 when limited to both.

Results: Search: identified 28 studies with data and plus a systematic review using STOPP/START criteria. For community dwelling-individuals for national outpatient databases (n=1,528,785) PIMs weighted average was 31%, PPOs 47%. For small community studies (n=2,228) PIMs weighted average was 26%, PPOs 24%. For hospitalised patients (n=4,237) PIMs weighted average was 47%, PPOs 50%. For nursing home patients PIMs weighted average (n=1,539 patients) was 59%, PPOs (n=463 residents) 49%. Principal PIMs were benzodiazepines, proton pump inhibitors, NSAIDs, aspirin, and duplicate medications. Principal PPOs were omissions of medications for cardiovascular diseases, hypertension, osteoporosis, diabetes and hyperlipidemia.

Conclusions: Rates of PIMs and PPOs are high. Criteria are currently based on expert consensus. Next steps are to link criteria to the best internationally-accepted evidence-based systematic reviews/guidelines and conduct RCTs to test whether application of the criteria leads to lower rates of medication errors and hospital admissions.