(previous session)

Matt Hirschey (Verdin Lab, UCSF-Gladstone): Lack of SIRT3 results in the metabolic syndrome. SIRT3 is a mitochondrial sirtuin (NAD+-dependent deacetylase) that is upregulated in liver upon fasting; knockout mice (SIRT3KO) are grossly normal but have trouble with lipid metabolism (specifically, beta-oxidation). Hershey identified several mitochondrial proteins involved in lipid oxidation that are deacetylated in response to fasting, in wildtype but not SIRT3KO. The knockouts are prone to developing obesity and metabolic syndrome with age.

Kate Brown (Chen lab, UC-Berkeley): Calorie restriction reduces oxidative stress by inducing SIRT3. Beginning with an invocation of the free radical theory of aging, and the observation that calorie restriction (CR) reduces oxidative stress, Brown asked whether the mitochondrial sirtuin SIRT3 could be involved in resistance to reactive oxygen species. She showed that CR induces SIRT3 expression, and that the SIRT3 protein deacetylates the mitochondrial antioxidant enzyme SOD2. Furthermore, consistent with Subhash Katewa’s talk in the first session, she demonstrated that CR reduces oxidative stress by switching from glucose to fatty acid oxidation, and that this switch requires SIRT3 activity.

(We’ve discussed SIRT3 before, most recently regarding its role as a tumor suppressor and also with respect to its relationship with exercise).

Ruth Tennen (Chua lab, Stanford): Insight into SIRT6 function at telomeres and beyond. Another member of the sirtuin family, SIRT6, is not localized to mitochondria but rather to telomeres, where it maintains telomeric chromatin in a healthy state and regulates the activity of the senescence-associated transcription factor NF-κB – for more background, see this previous post.) Tennen has shown that SIRT6 is involved in regulating the telomere position effect (TPE) – the silencing of gene expression caused by proximity to a telomere. The TPE has been implicated in age-related changes in gene expression: as telomeres shorten over time, telomere-proximal genes are aberrantly expressed — meanwhile, silencing factors are liberated to wander throughout the genome, repressing genes that should be turned on; similar logic has been applied to the relationship between DNA damage and transcriptional dysregulation.

Jue Lin (Blackburn Lab, UCSF): Telomere length maintenance and aging-related diseases. This talk described work that builds on significant progress, from this lab and others, demonstrating relationships between telomere length and stress, psychological outlook, and lifespan. Lin reviewed evidence that perceived stress is correlated with telomere length in white blood cells (consistent with previous results showing a relationship with intrusive thoughts). New-to-me data included a demonstration that people who increased omega-3 levels or made favorable lifestyle changes exhibited a slower rate of telomere shortening.

(next session)

Ouroboros

Animal studies support a cancer-promoting role for fat, and in humans, epidemiological data strongly suggest that dietary fat intake may be associated with incidence and mortality of cancers of the breast, colon, rectum, and prostate. There are also data implicating fat in cancers of the ovaries, uterus, pancreas, and lung, but the evidence is not as strong. There is still a debate as to whether it is total dietary fat, specific fats, or total calories that are involved in carcinogenesis. In any event, cancers of breast, colon, and prostate are highest in North America and western Europe and lowest in Asia, and are directly related to the intake of total fat in the diet even when adjusted for total calories. (more…)

Adipose tissue fat is not simply a reservoir for excess nutrients, but rather an active and dynamic organ capable of expressing biologically active fat-derived peptides (FDPs). At times of acute injury, macrophages contribute to the release of these peptides and the term inflammatory markers is often applied, but in the basal state, adipose tissue is the predominant source of production. Some of these FDPs may have a role in the development of the obesity metabolic syndrome of aging and other obesity-related diseases. (more…)

Concomitant with the global increase in obesity is the increase in the metabolic syndrome. The metabolic syndrome, also known as the metabolic syndrome of aging, syndrome X, and the insulin resistance syndrome, is a constellation of abnormal metabolism including glucose intolerance (impaired glucose tolerance, impaired fasting glucose, and type 2 diabetes & diabetes in elderly), central (abdominal) obesity in genes, dyslipidemia, and hypertension. (more…)

The principal reversible dementias are metabolic. Hypothyroidism and exposure to industrial or environmental toxins should be considered; iatrogenic cognitive impairment due to medications is a common example. Depending on the acuteness and intensity of the metabolic disturbance, the clinical presentation may be more similar to delirium than dementia. These dementias are reversible, but often not completely, depending on the length of exposure of the brain to the abnormal metabolic environment. (more…)

Obesity results from an imbalance between caloric consumption and caloric expenditure over a prolonged period. Weight gain occurs when there is a greater consumption of calories than expenditure. The expenditure of calories is complex and results from likely combinations of metabolic, genetic, and individual factors. Genetics and environment may predispose to weight gain, but it is only the consumption of calories in excess of utilization that can cause weight gain. (more…)

The accumulative waste theory of aging, also known as the waste accumulation or garbage accumulation theory of aging, proposes that molecules damaged by oxidation and their by products (e.g., aged collagen, damaged enzymes), and damaged mitochondria (organelles responsible for cellular energy production) accumulate in postmitotic (non dividing cells) causing dysfunction, toxicity, aging, and cell death (see Error Catastrophe Theory of Aging).

There are several mechanisms by which garbage accumulation affects cells. (more…)

The first line of defense belongs to a compound in the body called alpha lipoic acid (ALA). You may already know the importance I place on this multitasking, multi protective supplement. But recent studies have shown that it is even more powerful than previously thought.

Alpha lipoic acid is a very powerful antioxidant, anti-inflammatory agent, but additional amounts can be obtained only from (more…)

Potential benefits of T treatment in older men must be weighed against risks of adverse effects. In young hypogonadal men, physiological T replacement is low risk. In older men, risk–benefit ratios may be less advantageous. Minor adverse effects of T treatment include fluid retention, erythrocytosis, and sleep apnea, problems that may be more common in old men. Of greater concern are possible increases in atherosclerosis and greater risk of prostate cancer. (more…)